Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02950817 2016-12-07
AUTOMATIC INJECTION DEVICE
10
20 Field of the Invention
The present invention relates to an injection device for injecting a
substance,
such as a drug, into a patient.
Backgfte invention
One of the most common routes of administration for medications is by
injection,
such as intravenous, subcutaneous or intramuscular injection. A syringe
containing the
medication is used for the injection, which typically is carried out by
trained medical
personnel. In certain instances, a patient is trained in the use of the
syringe to allow for
self-injection. Moreover, certain medications are formulated in pre-filled
syringes for
patient use, to avoid the need for the patient to fill the syringe. Some
patients, however,
may be averse to carrying out self-injection, particularly if the patient has
a fear of
needles.
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2
Automatic injection devices offer an alternative to a syringe for delivering a
medication. Automatic injection devices have been used, for 'example, to
deliver
medications under emergency conditions, such as to administer epinephrine to
counteract the effects of a severe allergic reaction, for example, as caused
by a food
allergy. Automatic injection devices also have been described for use in
administering
antiarrhythmic medications and selective thrombolytic agents during a heart
attack (see
e.g., U.S. Patent Nos. 3,910,260; 4,004,577; 4,689,042; 4,755,169 and
4,795,433.
Various types of automatic injection devices also are described in, for
example, U.S.
Patent Nos. 3,941,130; 4,261,358; 5,085,642; 5,092,843; 5,102,393; 5,267,963;
6,149,626; 6,270,479; and 6,371,939.
In general, prior automatic injection devices, when operated, cause the needle
of
a syringe to move forward and project from a protective housing prior to
actuation of the
syringe to eject a dose of liquid through the needle. Movement of the syringe
toward the
patient's skin'such that the needle is exposed before pressurizing a liquid
charge inside
the syringe helps prevent-the liquid from dripping out of the needle before
the actual
injection takes place.
Such prior automatic injection devices have several disadvantages. For
example,
prior devices include an exposed needle that a patient is required to inject
into him or
herself, causing apprehension and anxiety for most patients, particularly
those patients
that are "needle phobic". Prior devices are also difficult for patients to
use, to maintain
free of contamination, and/or to provide an accurate dosage of medicine. In
addition,
patients suffering from chronic autaimmune diseases such as rheumatoid
arthritis, as
well as the elderly and physically disabled, may lack the dexterity needed to
self-
administer biologic therapies using existing injection devices. A need
therefore exists for
such self-medication delivery devices that patients are able to use safely and
that foster
patient adherence to their biologic therapy regimens.
= TNFa inhibitors -are effective in the treatment of atitoimmune disorders
such as
rheumatoid arthritis, psoriatic arthritis and Crohnes Disease. Such
inhibitors, which
include biological agents such as antibodies and antibody fusion proteins,
typically are
delivered by injection. The TNFa inhibitor adalimumab (HUMIRA1); Abbott
Laboratories, Lake County, Illinois), for example, has been marketed as a pre-
filled
syringe for self-administration by patients and therefore presents as an
important
candidate for use with an improved automatic injection devices and methods.
CA 02950817 2016-12-07
3
Summary of the Invention
The present invention provides improved devices, components thereof, and
methods of administering an injectable therapy to a patient. In an embodiment,
the
invention provides an automatic injection device for ejecting a dose of fluid
medication
from a needle of a syringe movably disposed within a housing of the device.
Prior to
use, the sYringe Of the invention is in a retracted position within the
housing. During a
first operational stage, initiated by actuating an activation button, an
actuator propels the
syringe towards a proximal end of the housing to project a needle of the
syringe from the
proximal end. In this first operational stage, the actuator causes the needle
to be inserted
into a subcutaneous region of the skin of the user when the proximal end of
the device is
held against an injection site. In a second operational stage, an actuator,
which may be
the same or a different component as the actuator that causes the needle to be
inserted,
causes the fluid disposed within the syringe to be ejected into the
subcutaneous region.
The automatic injection device of the invention may be used to inject a dose
of a
tumor necrosis factor-a (TNFa) inhibitor to treat any number of diseases,
including
rheumatoid arthritis, psoriasis, Crohn's disease, psoriatic arthritis, and
juvenile
rheumatoid arthritis. In one embodiment, the user has a disorder in which TNFa
is
detrimental selected from the group consisting of rheumatoid arthritis,
psoriasis, Crohn's
disease, ankylosing spondylitis,"psoriatic arthritis, and juvenile rheumatoid
arthritis.
The automatic injection device may include a window to allow a user to view
the
contents and/or level of the contents of the syringe. In addition, the
automatic injection
device may include an indicator to indicate when an injection is complete. A
"dummy"
or demonstration training automatic injection device may also be provided for
training a
user to use the automatic injection device to inject a substance without
actually injecting
a substance into the user.
The invention provides an automatic injection device for providing a
subcutaneous injection of a substance into a user or patient, comprising a
housing having
an open first end and a second end, a syringe movably disposed in the housing,
the
syringe including a barrel portion for holding the substance, a hollow needle
in fluid
communication with the barrel portion for ejecting the substance from the
syringe, and a
bung for sealing the barrel portion and selectively applying pressure to the
substance to
force the substance through the hollow needle, a syringe actuation component
for first
. moving the syringe towards the first end of the housing such that The
needle projects =
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from the first end and for subsequently applying pressure to the bung, the
syringe
actuation component including a pressurizer for selectively applying pressure
to the
bung, a compressible expanded central portion and a flange between a second
end of the
syringe actuation component and the compressible expanded central portion and
a first
biasing mechanism for biasing the syringe actuation component towards the
first open
end of the housing, the first biasing mechanism disposed between the flange of
the
syringe actuation component and the second end of the housing_
In one embodiment, the automatic injection device further comprises an
activation button disposed on the housing for actuating the syringe actuation
component.
In another embodiment, the automatic injection device includes an activation
button
coupled to the housing for actuating the syringe actuation component.
In another embodiment, the automatic injection device further comprises a
latch
actuated by the activation button for latching the syringe actuation component
in a
retracted position prior to actuation by the activation button.
The invention also includes an automatic injection device for providing a
subcutaneous injection of a substance into a user, comprising a housing having
an open
first end and a second end, a syringe movably disposed in the housing, the
syringe
including a barrel portion for holding the substance, a hollow needle in fluid
communication with the barrel portion for ejecting the substance from the
syringe, and a
bung for sealing the barrel portion and selectively applying pressure to the
substance to
force the substance through the hollow needle,an actuator for selectively
moving the
syringe towards a first end of the housing so that the needle extends from the
open first
end ofthe housing and an actuator for eNpelling the substance from the syringe
after
movement of the syringe towards the open first end of the housing. A first
removable
cap may cover the first end of the housing.
The actuator may include a first biasing mechanism, a second biasing
mechanism, a plunger-type syringe actuator and/or another actuator means.
In one embodiment, the automatic injection device further comprises a dose of
a
substance, e.g., a TNF inhibitor, loaded in the barrel portion of the syringe.
CA 02950817 2016-12-07
=
Included in the invention, is an automatic injection device for providing a
subcutaneous injection of a substance into a user, comprising a housing having
an open
first end, a second end and a window disposed in a side wall for viewing the
interior of
5 the housing, a syringe movably disposed in the housing, the syringe
including a barrel
portion for holding the substance, a hollow needle in fluid communication with
the
barrel portion for ejecting the substance from the syringe, and a bung rut
sealing the
barrel portion and selectively applying pressure to the substance to force the
substance
through the hollow needle, an actuator for selectively moving the syringe
towards a first
end of the housing so that the needle extends from the first end of the
housing and an
actuator for expelling the substance from the syringe after movement of the
Syringe
towards the first end of the housing.
In one embodiment, the window has a substantially key-hole shape. In a further
embodiment, the window includes a fill line at a position in the window for
indicating a
full doseof the substance.
The invention further provides an automatic injection device for providing a
subcutaneous injection of a substance into a user, comprising a housing having
an open
first end and a second end, a syringe movably disposed in the housing, the
syringe
including a barrel portion for holding the substance, a hollow needle in fluid
communication with the barrel portion for ejecting the substance from the
syringe, and a
bung for sealing the barrel portion and selectively applying pressure to the
substance to
force the substance through the hollow needle, a syringe actuation component
for
selectively applying pressure to the bung, the syringe actuation component
including a
pressurizer configured to be inserted into the barrel portion of the syringe,
a
compressible expanded central portion and an indicator disposed between the
compressible expanded central portion and a second end of the syringe
actuation
component for indicating when the contents of the syringe have been expelled.
The invention includes an automatic injection device for providing a
subcutaneous injection of 'a substance into a user, comprising a housing
having an open
first end, a second end and having a window formed in a side wall thereof, a
syringe
movably disposed within the housing for storing and selectively ejecting the
substance
from the open first end; and
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an indicator that aligns with the window in the side wall when the syringe is
substantially empty of the substance.
Another aspect of the invention includes an automatic injection device,
comprising a housing having a substantially tubular configuration with an open
first end
and a second end; a syringe movably disposed within the housing, the syringe
containing
a close of a substance, e.g., a TNF inhibitor, wherein the syringe moves
within the
housing to inject the TNF inhibitor into a user.
. In one embodiment, the automatic injection device further comprises an
indicator
for indicating when the substance, e.g., a TNF inhibitor, has been ejected
from the
syringe. =
In one embodiment, the automatic injection device further comprises a window
formed in the housing to allow viewing of the interior of the housing.
In one embodiment, the automatic injection device further comprises an
indicator
that aligns with the windnw when the substance, e.g., a TNF inhibitor, has
been ejected
from the syringe.
Another aspect of the invention is an automatic injection device for providing
a
subcutaneous injection of a substance into a user, comprising a housing having
an open
first end and a second end; a plunger including a rod configured to be
connected at a
first end to a bung of a Syringe, a compressible-expanded=central portion and
a flange
between a second end of the rad and the compressible expanded central portion;
and a
biasing mechanism for biasing the plunger towards the first open end of the
housing, the
biasing mechanism disposed about the second end of the rod between the flange
and the
second end of the housing.
In one embodiment, the automatic injection device further comprises an
activation button disposed on the housing for actuating the plunger.
In one embodiment, the automatic injection device further comprises a latch
actuated by the activation button for latching the plunger in a retracted
position prior to
actuation by the activation button.
In one embodiment of the invention, the automatic injection device further
comprises a window on the housing for viewing the interior of the housing.
In still another embodiment, the automatic injection device further comprises
an
indicator for indicating when the syringe is empty.. =
=
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7
In another embodiment, the automatic injection device comprises a syringe
comprising a dose of a substance, e.g., a 'INF inhibitor, to be injected into
a user.
In still another embodiment, the automatic injection device further comprises
a
removable cap for covering one of the first end and the second end of the
housing.
In one embodiment, the invention provides an automatic injection device
further
comprising a needle sheath that advances over the needle projecting through
the first end
after ejection of the substance from the syringe.
The invention features automatic injection device comprising a dose of a
TINIFoc inhibitor, e.gõ adalimurnab. In one embodiment, the automatic
injection device
further comprises a dose of a TNF inhibitor loaded in the barrel portion of
the syringe.
The invention includes a housing for an automatic injection device, comprising
a
hollow substantially tubular housing including an open first end and a second
end, the
hollow substantially tubular housing configured to slidably receive a syringe
therein; a
first stop in an interior surface of the housing for limiting movement of the
syringe in a
first direction; and a second stop on the interior surface of the housing for
limiting
movement of the syringe in a second direction.
In one embodiment, the housing further comprises a shelf formed between the
open first end and the first stop for seating a biasing mechanism for biasing
the syringe
away from the first end of the housing. In one embodiment, the housing further
comprises a window formed in a side wall of the housing for allowing viewing
of the
interior of the housing. In one embodiment, the housing further comprises an
activation
button disposed at the second end of the tubular housing for selectively
activating the
syringe to move from a first, retracted position to a second, projecting
position where a
needle of the syringe projects from the first end, and; while-the syringe is
in the second,
projecting position, apply pressure to eject a substance from the syringe.
The invention further includes a syringe for use in an automatic injection
device,
comprising a barrel portion for containing a substance; a hollow needle in
fluid
communication with the barrel portion; a bung for sealing the barrel portion,
the bung
movable within the barrel portion to increase pressure within the barrel
portion to force
the substance through the hollow needle; a first stop formed on an
intermediate portion
of the barrel portion for abutting a stop in a housing of the automatic
injection device to
limit movement of the syringe in a first direction; and a second stop formed
on a distal
end of the barrel portion for limiting movement of the syringe relative to the
housing of
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the automatic injection device in a second direction. In another embodiment,
the stops
may be formed at other locations throughout the barrel.
In one embodiment, the syringe further comprises a plunger for selectively
first
moving the syringe towards an open first end of the housing of the automatic
injection
device, such that the needle projects from the first end, and subsequently
applying
pressure to the bung to cause the syringe to eject the substance through the
hollow
needle.
In one embodiment, the plunger comprises a rod connected at a first end to the
bung and a compressible expanded central portion. In another embodiment, the
plunger
further includes an indicator for indicating when the syringe has ejected
substantially all
of the substance through the hollow needle. In one embodiment, the syringe
further
comprises a dose of a TNF inhibitor loaded in the barrel portion of the
syringe.
The invention further provides a syringe actuation component for an injection
device, comprising a rod portion having a first end, a second end and a
compressible
expanded central portion, and a pressurizer formed on the first end of the rod
portion
=
for applying pressure to a bung of a syringe. =
In one embodiment, the syringe actuation component further comprises an
anchoring portion formed on a second end of the rod portion for anchoring a
coil spring
to the syringe actuation component. In one embodiment, the syringe actuation
component further comprises an indicator for indicating completion of an
injection
formed in a solid rod portion between the compressible expanded central
portion and the
second end of the rod portion. In one embodiment, the syringe actuation
component
further comprises a retaining flange for holding the coil spring in a
compressed position
until actuation. In one embodiment, the syringe actuation component further
comprises
a spring base for the coil spring extending between the anchoring end and the
retaining
flange. In one embodiment, the. spring base comprises flexible legs around the
spring
coils. In another embodiment, the anchoring end comprises tabbed feet
extending from
the base and configured to releasably engage an activation button.
The invention further provides an article of manufacture comprising a
packaging
material and an automatic injection device comprising a TNFor. inhibitor. In
one
embodiment, the TNFa inhibitor comprises adalimumab. In one embodiment, the
dose
of adalimumab is 40 mg. The article of manufacture may also comprise an
alcohol prep
and/or a dose tray for holding the automatic injection device.
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9
= The invention also provides an article of manufacture comprising an
automatic
injection device having a pre-filled syringe containing a dose of a TNFcc
inhibitor; and
an alcohol preparation pod,. packaged with instructions for use to treat
arthritis by
injecting the dose into the skin of a user using the automatic injection
device.
The invention also provides an article of manufacture comprising: an automatic
injection device having a pre-filled syringe containing a dose of a TNFa
inhibitor; and
an alcohol preparation pad; packaged with instructions for use to treat
artluitis by
injecting the dose into the skin of a user using the automatic injection
device.
= The invention also includes a method of injecting a substance, comprising
the
steps of providing an automatic injection device comprising a housing having
an open
first end, a second end, a syringe movably disposed within the housing
containing the
substance, a cap covering the first end and a cap covering an activating
button on the
second end; removing the first cap; removing a second cap to expose ihe
activating
button; positioning the open first end of the device adjacent the skin of a
user; actuating
the activating button to cause a needle of the syringe to first project from
the open first
end and into the skin of the user and subsequently ejecting the substance
through the
needle an into a subcutaneous region of the user; and removing the device
after the
substance is ejected.
In one embodiment; the automatic injection device is held at about a 90 degree
angle relative to the skin of the user. In one embodiment, an indicator
provides an
indication to the user when the syringe is substantially empty of the
substance. In one
embodiment, the substance loaded and ejected from the syringe is a dose of a
TNF
inhibitor.
in still another embodiment of the invention, the method includes (a)
positioning
the automatic injection device at an injection site of the user; (b) engaging
the activator
mechanism to begin injection of the substance to the user; (c) maintaining
engagement
of the activator mechanism for a prescribed period of time to continue
injection of the
substance; and (d) removing the automatic injection device from the injection
site after
passage of the prescribed period of time.
In yet another embodiment of the invention, the method includes (a)
positioning
the automatic injection device at an injection site; (b) engaging the
activator mechanism
to begin injection of the substance to the user; (c) maintaining engagement of
the
activator'mechanistn. to continue injection' of the substance until, a visible
indicator of
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completion is detected; and (d) removing the automatic injection device from
the
injection site once the visible indicator of completion is detected.
The invention also features a method of training a recipient on use of an
automatic injection device.
5 One aspect of the invention is a device for training a recipient to use
an
automatic injection device, comprising a housing having a window, an
activation button
on a first end of the housing; and an indicator movably disposed within the
housing,
wherein the indicator aligns with the window of the housing after a user
activates the
activation button.
10 In an embodiment, the device further comprises an activation component
for
selectively moving the indicator fromi hidden position to a position aligned
with the
window. In one embodiment, the activation component comprises a rod having an
. = '
anchoring portion on a first end that is selectively latched by the activation
button, a
flanged portion for retaining a biasing mechanism towards the first end of the
housing,
and wherein the indicator is formed between a second end of the rod and the
flanged
portion.
The invention also provides a kit for training a recipient on use of an
automatic
injection device, wherein the automatic injection device comprises a needle
and a
medication, the kit comprising: (a) a demonstration automatic injection device
which
lacks the needle and the Medication; and (b) instructions for using the
automatic
injection device.
In one embodiment, the instructions convey a method to the recipient for using
the demonstration automatic injection device, the method comprising: (a)
position the
automatic injection device at an injection site; (b) engage the activator
mechanism to
begin injection of the medication; (c) Maintain engagement of the activator
mechanism
for a prescribed period of time to continue injection of the medication; and
(d) remove
the automatic injection device from the injection she after passage of the
prescribed
period of time.
In one embodiment, the prescribed period of time is 10 seconds. In another
embodiment, the prescribed period of time is at least 10 seconds.
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II
In one embodiment, the instructions further convey that initial engagement of
the
activator mechanism is accompanied by an audible sound.. In another
embodiment, the
instructions further convey that completion of injection of the medication is
accompanied by a visible indicator of completion.
In one embodiment, the instructions further convey that the injection site may
be
sterilized prior to positioning the automatic injection device at the
injection site.
In one embodiment, the instructions further convey that the automatic
injection
device be examined for proper dosage and formulation of the medication prior
to
positioning the automatic injection device at the injection site.
In one embodiment, the instructions further convey to the recipient, at least
one
message selected from the group consisting of: (a) the automatic injection
device is less
painful for a patient to use than a pre-filled syringe; (b) the automatic
injection device is
preferred for use by patients as compared to a pre-filled syringe; (c) the
automatic
injection device is easier to use by a patient than a pre-filled syringe; (d)
the automatic
-- injection device is more convenient for a patient to use. than a pre-filled
syringe; (e) the
automatic injection device reduces anxiety of patients with a fear of needles,
as
compared to a pre-filled syringe, since the needle is not visible in the
device; and (1) the
automatic injection device is designed to be easy to use from initial use of
the device.
In one embodiment, the recipient is a physician that prescribes the
medication.
-- In another embodiment, the recipient is a patient that uses the medication.
In yet another
embodiment, the recipient is a care-giver, such as a family member..
The invention also includes a demonstration automatic injection device
comprising
a housing having an open first end, a second end, and having a window formed
in a side
-- wall thereof,a syringe movably disposed within the housing; an activator
mechanism
associated with the syringe for depressing the syringe; and an indicator that
aligns with
the window in the side wall when the syringe is fully depressed.
The invention features an audiovisual device for promoting an automatic
injection device comprising a medication to a recipient, wherein the device
conveys to
-- the recipient at least one message selected from the group consisting of:
(a) the
automatic injection device is less painful for a patient to use than a pre-
filled syringe; (b)
the automatic injection device is preferred for use by patients as compared to
a pre-filled
syringe; (c) the automatic injection device is easier to use by a patient than
a pre-filled
CA 02950817 2016-12-07
12
syringe; (d) the automatic injection device is more convenient for a patient
to use than a
pre-filled syringe; (e) the automatic injection device reduces anxiety of
patients with a
fear of needles, as compared to a pre-filled syringe, since the needle is not
visible in the
device; and (0 the automatic injection device is designed to be easy to use
from initial
use of the device.
The invention also includes an audiovisual device or printed material for
training
a recipient on the use of an automatic injection device, wherein the automatic
injection
device comprises an activator mechanism and a medication, the audiovisual
device
conveying to the recipient instructions to: (a) position the automatic
injection device at
an injection site; (b) engage the activator mechanism to begin injection of
the=
medication; (e) maintain engagement of the activator mechanism for a
prescribed
period of time to continue injection of the medication; and (d) remove the
automatic
injection device from the injection site after passage of the prescribed
period of time.
The invention also includes an audiovisual device or printed material for for
training a recipient on the use of an automatic injection device, wherein the
automatic
injection device comprises an activator mechanism and a medication, the
audiovisual
device conveying to the recipient instructions to: (a) position the automatic
injection
device at an injection site; (b) engage the activator mechanism to begin
injection of the
medication; (c) maintain engagement of the activator mechanism to continue
injection
of the medication until a visible indicator of completion is detected; and (d)
remove the
automatic injection device from the injection site once the visible indicator
of
completion is detected.
The invention further provides a method of training a recipient on the use of
an
automatic injection device, wherein the automatic injection device comprises
an
activator mechanism and a medication. The method comprises, in one embodiment,
conveying to the recipient instructions to: (a) position the automatic
injection device at
an injection site; (b) engage the activator mechanism to begin injection of
the
medication; (c) maintain engagement of the activator mechanism to continue
injection of
the medication until a visible indicator of completion is detected; and (d)
remove the
automatic injection device from the injection site once the visible indicator
of
completion is detected.
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13
In one embodiment, the automatic injection device comprises an indicator
window and the visible indicator of completion comprises a color indicator,
e.gõ yellow,
appearing in the indicator window.
In one embodiment, the instructions further convey that initial engagement of
the
activator mechanism is accompanied by an audible sound.
In one embodiment, the instructions further convey that engagement of the
activator mechanism is maintained for a prescribed period of time, e.g., 10
seconds, to
continue injection of the medication. In one embodiment, the instructions
further
convey that the injection site be sterilized prior to positioning the
automatic injection
.10 device at the injection site.
In one embodiment, the instructions further convey that the automatic
injection
device be examined for proper dosage and formulation of the medication prior
to
positioning the automatic injection device at the injection site.
In another aspect, the invention pertains to a method of training a user on
the use
of an automatic injection device, wherein the automatic injection device
comprises a
needle and a medication, the method comprising providing to the user: (a) a
demonstration automatic injection device which lacks the needle and the
medication;
and (b) instructions for using the automatic injection device.
In yet another aspect, the invention pertains to a kit for training a
recipient on the
use of an automatic injection device comprises a needle and a medication, the
kit
comprising: (a) a demonstration or "trainer" automatic injection device which
lacks the
needle and the medication; and (b) instructions for using the automatic
injection device.
In yet another aspect, the invention pertains to a method of training a
recipient on
the use of an automatic injection device, wherein the automatic injection
device
comprises an activator mechanism and a medication. The training method
comprises
conveying to the recipient instructions to: (a) position the automatic
injection device at
an injection site; (b) engage the activator mechanism to begin injection of
the
medication; (c) maintain engagement of the activator mechanism for a
prescribed period
of time to continue injection of the medication; and (d) remove the automatic
injection
device from the injection site after passage of the prescribed period of time.
Preferred prescribed periods of time for engaging the activator mechanism
include 10 seconds, or engaging the activator mechanism for at least 10
seconds. In
certain embodiments, the instructions further convey that initial engagement
of the
CA 02950817 2016-12-07
14
activator mechanism is accompanied by an audible sound. In certain
embodiments, the
instructions further convey that completion of injection of the medication is
accompanied by a visible indicator of completion. In certain other
embodiments, the
instructions further convey that the injection site be sterilized prior to
positioning the
automatic injection device at the injection site. In certain embodiments, the
instructions
further convey that the automatic injection device should be examined for
proper dosage
and formulation of the medication prior to positioning the automatic injection
device at
the injection site.
In another aspect, the invention pertains to a method of training a recipient
on the
use of an automatic injection device, wherein the automatic injection device
comprises
an activator mechanism and a medication. The training method comprises
conveying to
the recipient instructions to: (a) position the automatic injection device at
an injection
site; (b) engage the activator mechanism to begin injection of the medication;
(c)
maintain engagement of the activator mechanism to continue injection of the
medication
until a visible indicator of completion is detected; and (d) remove the
automatic
injection device from the injection site once the visible indicator of
completion is
detected. '
In a preferred embodiment, the automatic injection device comprises an
indicator
window and the visible indicator of completion comprises a 'color indicator
appearing in
the indicator window. The color indicator can be, for example, a yellow color
indicator.
In one embodiment, the instructions are provided in a printed document or in
an
audiovisual device. In another embodiment, the audiovisual device is a Video
Home
System (VHS) cassette or a Digital Video Disc (DVD). In one embodiment, the
instructions are conveyed orally to the recipient.
In one embodiment, the recipient is a physician that prescribes the
medication.
In one embodiment, the recipient is a patient that uses the medication.
The invention also includes an article of manufacture comprising a packaging
material; a TNFct inhibitor, such as adalimumab; and a label or package insert
contained
within the packaging material indicating that in studies of the TNFcc
inhibitor using the
automatic injection device of the invention for the treatment of a disorder in
which
TNFct is detrimental, such as rheumatoid artitiitis, the most common adverse
events
(AEs) were bronchitis, hypersensitivity, arthritic pain, cough and rhinitis.
CA 02950817 2016-12-07
The invention further provides an article of manufacture comprising: a
packaging
material; an automatic injection device, e.g., an autoinjector pen filled with
a
TNFtx inhibitor; and a label or package insert contained within the packaging
material
indicating that the bioequivalence of the TNFa inhibitor is similar regardless
of whether
5 the injection site is the thigh or abdomen.
The article of manufacture of the invention may comprise a label. In one
embodiment, the label of the invention indicates how the TNFa inhibitor, e.g.,
TNF
antibody, or antigen binding portion thereof, is packaged as an article of
manufacture.
In one embodiment, the label of the invention indicates the ThiFot inhibitor,
e.g., INF
10 antibody, or antigen binding portion thereof, is dispensed in a carton
containing 6
alcohol preps and 6 dose trays (e.g., labeled Crohn's Disease Starter
Package). In
another embodiment, the label indicates that each dose tray consists of a
single-use pen
each pen, containing a 1 mL prefilled glass syringe with a fixed 27 gauge 1/2
inch needle,
providing 40 mg (0.8 mL) of the TNFcx inhibitor.
15 The present invention relates to automatic injection devices for
administering
medications and in particular relates to compositions and methods for
promoting the use.
of such devices and to compositions and methods for training users (e.g.,
patients and
medical personel) in the use of such devices. The invention is based, at least
in part, on
results of a clinical study comparing an automatic injection device for
administering
adalimumab (FIIJM1R" to a pre-filled syringe for administering adalimumab
(HUMIRA4 ). The study revealed numerous advantageous features of the aUtomatic
injection device and identified particular aspects of using the device to be
highlighted
when training someone to use the device.
Accordingly, in one aspect, the invention pertains to a method of promoting an
automatic injection device comprising a medication to a recipient. The method
comprises conveying to the recipient at least one message selected from the
group
consisting of:
(a) the automatic injection device is less painful for a patient to use than a
pre-filled
syringe;
(b) the automatic injection device is preferred for use by patients as
compared to a pre-
filled syringe; (c) the automatic injection device is easier to use by a
patient than a pre-
filled syringe; (d) the automatic injection device is more convenient for a
patient to use
than a pre-filled syringe; (e) the automatic injection device reduces anxiety
of patients
CA 02950817 2016-12-07
16
with a fear of needles, as compared to a pre-filled syringe, since the needle
is not visible
to the user while using the device; and (f) the automatic injection device is
designed to
be easy to use from the initial use of the device.
In a preferred embodiment, the message conveyed to the user is that the
automatic injection device is less painful for a patient to use than a pre-
filled syringe, for
example that 80% of patients in a clinical trial rated the automatic injection
device as
less painful than a pre-filled syringe. In another preferred embodiment, the
message
conveyed to the recipient is that the automatic injection device is preferred
for use by
patients as compared to a pre-filled syringe, for example that 90% of patients
in a
clinical trial preferred the automatic injection device to a pre-filled
syringe.
In certain embodiments, the user is conveyed the information that the
automatic
injection device comprises a five bevel needle, as compared to a three bevel
needle for a
pre-filled syringe.
In another aspect, the invention pertains to an audiovisual device for
promoting
an automatic injection device comprising a medication to a user, wherein the
device
conveys to the user at least one of the messages provided above. In the
methods and
compositions of the invention, the promotional messages or training
instructions can be
conveyed, for example, orally to the recipient and/or in writing to the
recipient.
Alternatively or in addition, the audiovisnal device can be, for example, a
Video Home
System (VHS) cassette or a Digital Video Disc (DVD).
In the methods of the invention, the recipient of the promotional messages or
training instructions can be, for example, a physician that prescribes the
medication, a
patient that uses the medication, or a caregiver.
In the methods and compositions of the invention, preferably the automatic
injection device provides for subcutaneous injection of the medication.
Preferred
embodiments of the automatic injection device are described herein.
The automatic injection device used in the methods and compositions of the
invention may comprise a substance or medication that is, for example, an
antibody, a
cytokine, a vaccine, a fusion protein or a growth factor. In a preferred
embodiment, the
medication is a TNFa inhibitor (e.g., an anti-INF antibody or an antigen-
binding
portion thereof, a INF fusion protein, or a recombinant 'TNF binding protein),
such as
infliximab (RemicadeTM, Centocor, Horsham, PA), CDP 571, COP 870, anti-INF
dAb,
golimumab, adalimumab, etanercept (EnbrelTM, Amgen, California), p55TNFR I gG
CA 02950817 2016-12-07
17
(Lenercept) or r-TBP-1. A particularly preferred medication for use in the
automatic
injection device is adalimumab (HUMIR". Another particularly preferred
medication
foruse. in the automatic injection device is an isolated human antibody that
dissociates
from human TNFcc with a Kd of 1 x 10-8 M or less and a Koff rate Constant of 1
x l0-3 s-
I or less, both determined by surface plasmon resonance, and neutralizes human
TNFct
cytotoxicity in a standard in vitro L929 assay with an IC50 of 1 x 10-7 M or
less. In one
embodiment, the automatic injection device, including uses and compositions
thereof,
comprises a dose of a TNFoc inhibitor.
In one embodiment, the anti-TNFa antibody, or antigen-binding portion thereof,
is selected from the group consisting of a chimeric antibody, a humanized
antibody, a
human antibody, and a multivalent antibody..
In one embodiment, the anti-TNFa antibody is an isolated human antibody, or
antigen-binding portion thereof, with the following characteristics: a)
dissociates from
human TNFa with a Koff- rate constant of I x 10 s-1 or less, as determined by
surface
plasmon resonance; b) has a light chain CDR3 domain comprising the amino acid
=
sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine
substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino
acid
substitutions at positions 1, 3, 4, 6,7, 8 and/or 9; and c) has a heavy chain
CDR3 domain
comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID
NO: 4
by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or
by one to five
conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11
and/or 12.
In one embodiment, the anti-TNFa antibody is an isolated human antibody, or an
antigen binding portion thereof, with a light chain variable region (LCVR)
comprising
the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region
(HCVR)
comprising the amino acid sequence of SEQ ID NO: 2
In one embodiment, the anti-TNFa antibody, or antigen-binding portion thereof,
is selected from the group consisting of infliximab, golimumab, and adalimumab
In one embodiment, the TNFa inhibitor is selected from the group consisting of
infliximab, CDP 571, CDP 870, anti-TNF dAb, golimumab, adalimumab, etanercept,
p55TNFR1gG and r-TBP-1.
In one embodiment, the substance that is loaded into the automatic injection
device is a formulation comprising adalimumab, sodium chloride, monobasic
sodium
CA 02950817 2016-12-07
18
phosphate dihydrate, dibasic sodium phosphate dihydrate, sodium citrate,
citric acid
monohydrate, mannitol, polysorbate 80, and water.
In one embodiment, the automatic injection device is used to deliver an anti-
TNFa antibody, or antigen-binding portion thereof, to a used, wherein
administration is
given on a biweekly dosing regimen or a multiple variable dose regimen.
Brief Description of the Figures
The foregoing and other objects, features and advantages of the present
invention, as well as the invention itself, will be more fully understood from
the
following description = of preferred embodiments when read together with the
accompanying drawings, in which:
Figure 1 is a perspective view of the automatic injection device according to
an
illustrative embodiment of the invention.
Figure 2 is an exploded view of the automatic injection device according to an
illustrative embodiment of the invention.
Figure 3 is a cross-sectional schematic view of an automatic injection device
of
an embodiment of the invention prior to use.
Figure 4 is a cross-sectional schematic view of the automatic injection device
of
Figure 3 during a subsequent stage of operation.
Figure 5 is a cross-sectional schematic view of the automatic injection device
of
Figure 3 during a final stage of operation. =
Figure 6 illustrates an embodiment of an automatic injection device according
to
one embodiment of the invention.
Figure 7 is an exploded view of the firing mechanism assembly of the automatic
injection device of Figure 6 according to an illustrative embodiment of the
invention.
Figures 8A-8C are different views illustrating the distal housing component,
coil
spring and syringe actuation component of the firing mechanism assembly of
Figure 7
when assembled without the activation button.
Figure 9 is a perspective view of the distal housing component of the firing
mechanism assembly of Figure 7.
Figure 10 is a perspective view of the syringe actuation component of the
firing
mechanism assembly of Figure 7.
CA 02950817 2016-12-07
19
Figure 11 is an exploded view of the syringe housing assembly of the automatic
injection device of Figure 6 according to an illustrative embodiment of the
invention.
Figure 12 illustrates an embodiment of the syringe carrier of the syringe
housing
assembly of Figure 11.
Figure 13 illustrates an embodiment of the stepped shroud of the syringe
housing
assembly of Figure 11.
Figure 14 illustrates an embodiment of the proximate cap of the syringe
housing
assembly of Figure 11.
Figures 15a and 15b are a perspective side view and a cross-sectional side
view,
respectively, of the assembled spring housing assembly of Figure 11 according
to one
embodiment of the invention.
Figures 16A and 1613 are cross-sectional views at 90 degree offset angles from
each other, illustrate an assembled automatic injection device, wherein a
syringe housing
assembly and a firing mechanism assembly are coupled together.
Figure 17 is a detailed view of the interface between a syringe housing
assembly
and a firing mechanism assembly of an automatic injection device of an
embodiment of
the invention, illustrating the indicator of the syringe actuation component
according to
one embodiment of the invention.
Figures 18-22 are cross-sectional view of an automatic injection device
according to another embodiment of the invention.
Figure 23 is a detailed view of the display window of an automatic injection
device according to one embodiment of the invention.
Figure 24 illustrates use of an automatic injection device of an illustrative
embodiment of the invention to inject a drug, such as a TNF inhibitor, into a
subcutaneous region of a user.
Figure 25 illustrates a diagram of thd autoinjection pen for self-
adniinistraticin of
adalimumab:
Figure 26 shows results of final patient preference survey following Visit 3,
Figure 27 shows results showing the likelihood of switching to pen and
likelihood of recommending the pen to others.
Detailed Description of the Invention
CA 02950817 2016-12-07
The present invention provides automatic injection devices , components
thereof,
and methods for injecting a substance, such as a liquid drug, into a patient
to manage or
cure a medical condition. In one embodiment, the automatic injection device is
a pen,
i.e., an autoinjector pen or autoinjection pen (used interchangeably herein).
The present
5 invention also provides a demonstration or "trainer" automatic injection
device, which
may be used to train a patient how to use an automatic injection device.
The present invention also relates to automatic injection devices for
administering substances (also referred to herein as medications) and in
particular relates
to compositions and methods for promoting the use of such devices and to
compositions
10 and methods for training people in the use of such devices. The
invention is based, at
least in part, on results of a clinical study comparing an automatic injection
device for
administering adalimurnab (}{UMIRA ) to a pre-filled syringe for administering
adalinnunab (HUMIRA6). The study, described in detail in Examples 1 and 2
herein,
revealed numerous advantageous features of the automatic injection device of
the
15 invention and identified particular aspects of methods.of using the
device that should be
highlighted when training a recipient to use the device.
1. Definitions
= So that the invention may be more readily understood; certairi terms are
defined,
20 as follows:
As used herein, an "automatic injection device" (or "autoinjector") is
intended to
refer to a device that enables an individual (also referred to herein as a
user or a patient)
to self-administer a dosage of a substance, such as a liquid medication,
wherein the
device differs from a standard syringe by the inclusion of a mechanism for
automatically
delivering the medication to the individual by injection when the mechanism is
engaged.
As used herein, the term "pre-filled syringe" is intended to encompass a
syringe
that is filled with a medication immediately prior to administration of the
medication to
an individual and a syringe that is filled with a medication and stored in
this pre-filled
form for a period of time before administration of the medication to an
Individual.
As used herein, a "recipient" is intended to refer to any person or individual
that
receives the promotional messages or training instructions of the methods and
compositions of the invention described herein. Preferred recipients include
physicians
that prescribe the medication to be administered by the automatic injection
device, and
CA 02950817 2016-12-07
21
patients that use the medication to be administered by the automatic injection
device,
and their caregivers.
As used herein, the term "conveying to the recipient" is intended to encompass
any means by which a promotional message or training instruction of the
methods and
compositions of the invention described herein is communicated to or expressed
to a
recipient. Non-limiting examples of means for conveying a message or
instruction to a
recipient include oral communication, written communication and communication
via an
audiovisual device.
As used herein, the term "initial use of the device" is intended to refer to
the first
time the automatic injection device is used to administer a substance, e.g., a
medication,
to an individual.
As used herein, the term "printed document" is intended to refer to any
document
that has written communication printed on it. Non-limiting examples of printed
documents include brochures, leaflets, product inserts, flyers, flipcharts,
tent cards and
package labels.
As used herein, the term "audiovisual device" is intended to refer to any
device
that is capable of communicating information in auditory and visual form. Non-
limiting
examples of audiovisual devices include Video Home System (VHS) cassettes,
Digital
Video Discs (DVDs), CD-ROMS, digital videocassettes, 8mm or 35 mm films and
computers displaying Webcasts.
As used herein, the term "demonstration automatic injection device" or "a
device
for training" or "trainer" is intended to refer to an automatic injection
device that is used
to demonstrate the procedurefor using the automatic injection device,
ineludingtht look
and feel of using the device, but which is not suitable for administering a
substance, e.g.,
a medication, because it lacks one or more necessary components for
administration of a
substance, e.g., a medication and/or a needle. In a preferred embodiment, the
demonstration automatic injection device lacks a needle and the substance,
e.g., a
medication, as compared to the automatic injection device.
IL Automatic Injection Device of Invention
The invention will be described below relative to certain illustrative
embodiments. While the present invention is described with respect to using
the device
to provide a subcutaneous injection of a dose of a TNF inhibitor, one skilled
in the art
CA 02950817 2016-12-07
22
will recognize that the invention is not limited to the illustrative
embodiment, arid that
the injection device may be used to inject any suitable substance into a user.
In addition,
the components and the method of using the automatic injection device are not
limited to
the illustrative embodiments described below.
As used herein, the term "distal" refers to the portion or end of an automatic
injection device or component in the automatic injection device furthest from
an
injection site of the user when the device is held against the person for an
injection or for
mimicking an injection. The term "proximal" refers to the portion or end of an
automatic injection device or a component of the automatic injection device
closest to an
injection site of the user during an injection.
Figures 1 and 2 superficially illustrate an automatic injection device 10
suitable
for subcutaneously injecting a dose of a substance, such as a liquid drug,
into a patient
according to an illustrative embodiment of the invention. The automatic
injection device
10 inthides a housing 12 for housing a container, such as a syringe,
containing a dose of
a substance to be injected into a patient, as described in detail below. The
housing 12
preferably has a tubular configuration, though one skilled in the art will
recognize that
the housing 12 may have any suitable size, shape and configuration for housing
a
syringe or other container of a substance to be injected. While the invention
will be
described with respect to a syringe mounted in the housing 12, one skilled in
the art will
recognize that the automatic injection device 10 may employ any suitable
container for
storing and dispensing a substance.
Referring to Figure 2, the syringe is preferably slidably mounted in the
housing
12, as described in detail below. In an inactivated position, the syringe is
sheathed and
retracted within the housing 12. When the device is actuated, a needle of the
syringe
projects from a first (proximal) end 20 of the housing 12 to allow ejection of
a substance
from the syringe into a patient. As shown, the first end of the housing 20,
i.e., the
proximal end, includes an opening 28 through which the needle of the syringe
projects
during actuation of the device 10.
Continuing to refer to Figures 1 and 2, a second (distal) end 30 of the
housing 12,
i.e., the distal end, includes an activation button 32 for actuating the
syringe to move
from a sheathed position within the housing 12 to a projecting position, and
subsequently to expel the substance from the needle into the patient. The
housing 12
CA 02950817 2016-12-07
23
houses one or more actuators that perform the functions of moving the syringe
and
expelling the substance from the syringe.
The illustrative automatic injection device 10 shown in Figures 1 and 2 may
also
include a first removable cap 24 (or needle cap) for covering the first end 20
of the
housing 12, to prevent exposure of the needle in the syringe prior to use. In
the
illustrative embodiment, the first cap 24 may include a boss 26 for locking
and/or
covering the interior components of the device 10 until the user is ready to
activate the
device 10. Alternatively, the first cap 24 may comprise a threaded screw
portion and the
internal surface of the housing 12 at opening 28 may comprise screw thread.
Any
suitable mating mechanism may be used in accordance with the teachings of the
invention.
A second removable cap 34 (or actuator cap) may cover the second end 30 of the
housing 12 to prevent accidental actuation of the activation button 32.
The second cap 34 may have a distinctive color to differentiate the first end
20
and second end 30 of the device, though one skilled in the art will recognize
that the cap
34 and housing 12 may have any suitable color, size and configuration.
In the illustrative embodiment of Figures 1 and 2, the housing 12 and caps 24
and 34 may further include graphics, symbols and/or numbers to. facilitate use
of the
automatic injection device 10. For example, in the illustrative embodiment,
the housing
12 includes an arrow 125 on an outer surface pointing towards the first end 20
of the
device to indicate how the device 10 should be held relative to the patient
(i.e., with the
first end 20 adjacent to the injection site), as shown in Figure 2. In
addition, the first cap
24 is labeled with a "1" to indicate that a user should remove the first cap
24 of the
device first, and the second cap is labeled with a "2" to indicate that the
second cap 34
should be removed after the first cap 24 is removed during preparation for and
subsequent injection using the illustrative automatic injection device 10. One
skilled in
the art will recognize that the automatic injection device 10 may have any
suitable
graphics, symbols and/or numbers to facilitate user instruction, or the
automatic
injection device may omit such graphics, symbols and/or numbers.
As shown in Figure 2, the first end 20 of the housing 12 may have a wider
diameter than the second end 30. A step 29 may be formed at the transition
between the
two diameters to accommodate the second cap 34 to facilitate seating of the
second cap
34 on the second end 30 of the housing.
CA 02950817 2016-12-07
24
As illustrated in Figures 1 and 2, the housing 12 also preferably includes a
display window 130 to allow a user to view the contents of the syringe housed
within the
housing 12, as described in detail below. The window 130 may comprise an
opening in
the sidewall of the housing 12, or may comprise a translucent material in the
housing 12
to allow viewing of the interior of the deviert 10.
The housing 12 may be formed of any suitable surgical material, including, but
not limited to, plastic and other known materials. =
Figures 3-5 are schematic views of interior components of an automatic
injection
device 10 according to one embodiment of the invention. As shown, a sytinge 50
or
other suitable container for a substance is disposed within the interior of
the housing 12.
The illustrative syringe 50 includes a hollow barrel portion 53 for holding a
dose of a
liquid substance to be injected. The illustrative barrel portion 53 is
substantially
cylindrical in shape, though one skilled in the art will recognize that the
barrel portion
53 may have any suitable shape or configuration. A seal, illustrated as a bung
54, seals
the dose within the barrel portion 53. The syringe 50 may further include a
hollow
needle 55 connected to and in fluid communication with the barrel portion 53,
through
which the dose can be ejected by applying pressure to the bung 54. The hollow
needle
55 extends from a first, proximal end 53a of the barrel portion 53. The second
end 53b
of the barrel portion 53 includes a flange 56, or other suitable mechanism,
for abutting a
stop, represented schematically as 123, in the housing 12 to limit the
movement of the
syringe 50 within the housing 12, as described below. One skilled in the art
will
recognize that the invention is not limited to the illustrative embodiment of
the syringe
50 and that any suitable container for containing a dose of a substance to be
injected
may be used in accordance with the teachings of the invention. In the
illustrative
embodiment of Figures 3-5, the needle 55 is a fixed twenty-seven gauge one-
half inch
needle. The tip of the illustrative hollow needle 55 may include five bevels
to facilitate
insertion. However, the needle 55 may have any suitable size, shape and
configuration
suitable for piercing a user's skin to deliver a substance to a subcutaneous
region and is
not limited to the illustrative embodiment. Suitable types of needles are well-
known in
the art.
The automatic injection device 10 shown in Figures 3-5 further includes a
syringe actuator, illustrated as a plunger 70, for selectively moving and
actuating the
syringe 50 to inject the dose contained in the syringe 50 into a user. The
illustrative
CA 02950817 2016-12-07
=
plunger 70 includes a rod portion 71 having a first end 71a integral with,
connected to or
in fluid communication with the bung 54 for selectively applying pressure to
the bung
54 to expel the dose from the needle 55. The plunger 70 may include a flanged
second
end 72.
5 . In an
embodiment, the syringe activator comprises multiple components and/or
more actuators are present in the automatic injection device of the invention.
= The plunger 70 of Figures 3-5 is biased forward towards the first end 20
of the
device 10 by a first biasing mechanism, illustrated as a coil spring 88
disposed about or
above a flanged second end of the plunger 70. In the embodiment illustrated in
Figures
10 -- 3-5, a proximate end 88a of the coiled spring 88 abuts the flanged
second end 72 of the
plunger 70 to selectively apply pressure and move the plunger 70 proximally.
Alternatively, the plunger 70 extends through the center of the spring 88.
Prior to use of
the device 10, the coil spring 88 (or another suitable mechanism)is compressed
between
the plunger 70 and the housing 12, storing energy. A trigger 91, which is
activated by
15 -- any suitable actuation means, such as the activation button 32 shown in
Figures 1 and 2,
retains the plunger 70 and first biasing mechanism 88 in a retracted, latched
position,
shown in Figure 3, the activation button 32 is activated. In the illustrative
embodiment,
the trigger 91 latches the flanged second end 72 of the plunger 70. When a
user
activates the activation button 32 or other actuation means, the trigger 91
releases the
20 -- flanged second end 72 of the plunger 70, allowing the coil spring 88,
which applies
pressure to the flanged second end 72, to propel the plunger 70 towards the
first end of
the device 10.
A second biasing mechanism, illustrated as a coil spring 89 in Figures 3-5,
holds
the syringe 50 in a retracted position within the housing 12 prior to use, as
shown in
25 -- Figures 1 and 3. In the retracted position, the needle 55 is preferably
sheathed entirely
within the housing 12. The illustrative syringe coil spring 89 is disposed
about the
proximal portion of the barrel portion 53 and may be seated in a shelf 121
formed within
the housing interior. The top end of the coil spring 89 abuts the flanged
second end 56
of the syringe 50. = The spring force of the' second biasing mechanism 89
pushes the
flanged second end 56 of the syringe 50 away from the first end 20 of the
housing 12,
thereby holding the syringe 50 in the retracted position until activated.
Other
components of the device 10 may also position the syringe 50 relative to the
housing 12.
CA 02950817 2016-12-07
26
The first biasing mechanism 88 and the second biasing mechanism 89 may have
any suitable configuration and tension suitable for use in biasing certain
components of
the device. For example, the first biasing mechanism 88 has any suitable size,
shape,
energy and properties suitable for moving the plunger 70 and syringe 50
forward when
released. The second biasing mechanism 89 has any suitable size, shape, energy
and
properties suitable for retracting the syringe 50 prior to activation. Other
suitable means
for facilitating movement and expulsion from the syringe.may also be used.
Referring still to the illustrative embodiment of Figures 3-5, the plunger 70
further includes a compressible expanded central portion 76. In the
illustrative
embodiment, the rod 71 is split in the central portion to form a pair of
projecting elbows
78 that define the compressible expanded central portion 76. The projecting
elbows 78
may be pre-formed as part of the molded plunger 70, or may be attached to the
plunger
70 separately. The projecting elbows 78 are compressible, so that they can be
moved
radially inwardly to cause that portion of the rod to adopt a circumference
similar to the
rest of the rod. The compressible expanded central portion 76 facilitates
movement, of
the syringe 50, followed by expulsion of the dose in two substantially
separate stages, as
'described below.
As shown in Figure 4, when an activation means 320 activates the trigger 91 to
release the plunger 70, the spring force of the coil spring 88 propels the
plunger 70
forward (proximally). During a first operational stage, the moving plunger 70
pushes
the syringe 50 forward, such that the tip of the needle 55 projects from the
first end 20 of
the housing 12. The initial biasing force provided by the first coil spring 88
is sufficient
to overcome the biasing force of the second coil spring 89 to allow movement
of the
syringe 50 against the backward biasing force of the second coil spring 89. In
the first
operational stage, the expanded region 76 of the plunger 70, formed by the
projecting
elbows 78, rests against the second end 56 of the barrel portion 53,
preventing the
plunger 70 from traveling within the syringe barrel portion 53. In this
manner, all
biasing force from the first coil spring 88 is applied to move the syringe 50
forward
towards the first end 20 of the device 10.
The activation means 320 illustrated in Figures 3-5 may have any suitable
size,
shape, configuration and location suitable for releasing the plunger 70 or
otherwise
activating the device 10. For example, still referring to Figure 2, the
activation means
320 may be an 'activation button 32 formed on a distal end 30.of the housing
12, or may
CA 02950817 2016-12-07
27
comprise another suitable device, such as a latch, twist-activated switch and
other
devices known in the art. While the illustrative activation means 320 is
located towards
a distal end 30 of' the device 10, one skilled in the art will recognize that
the activation
means 320 may be positioned in any suitable location on the device 10.
The forward motion of the syringe 50 towards the proximal end 20 of the device
continues against the biasing force of the coil spring 89 until the flanged
end 56 of
the barrel portion 53 abuts a stop 123, such as a protrusion or flange, on the
housing 12,
as shown in Figure 4. One skilled in the art will recognize that alternate
stopping or
limited mechanisms may be employed and that the invention is not limited to
the
10 illustrative stopping mechanism.
As shown in Figure 4, the first operational stage propels the tip of the
needle 55
through the opening 28 at the first end 20 of the device 10, so that the
needle 55 may
.pierce the skin of a patient. During this stage, the syringe barrel portion
53 preferably
remains sealed without expelling the substance through the needle 55. The
interference
caused by the stopping mechanisms 56, 123 maintains the needle 55 in a
selected
position extending from the proximal open end 28 of the device 10 during
subsequent
steps. Until the stopping mechanisms 56, 123 stop the movement of the syringe
50, the
compressible expanded central portion 76 of the plunger 70 prevents movement
of the
plunger 70 relative to the barrel portion 53.
The stops 56, 123 may be positioned at any suitable location relative to the
open
first end 20 to allow the syringe 50 to penetrate the skin by any suitable
depth suitable
for an injection.
In the second operational stage, which commences after the stopping mechanism
123 housing 12 catches the flanged portion 56, or other stopping mechanism,
stopping
further movement of the barrel portion 53, the continued biasing force of the
coil spring
88 continues to push the plunger 70 relative to the housing 12, as shown in
Figure 5.
The biasing force causes the elbows 78 of 'the plunger 70 to compress radially
inward
and slide into the interior of the barrel portion 53. While the interference
between
components 123 and 56 retains the barrel portion 53 in a selected position
(with the
needle exposed) and with the elbows 78 in a collapsed stage, the coil spring
88 pushes
the plunger 70 within the barrel portion. After the plunger 70 overcomes the
necessary
force to allow the elbows 78 to compress and extend into the barrel portion
53, the
plunger 70 applies pressure to the bung 54, causing ejection of the contents
of the
CA 02950817 2016-12-07
28
syringe 50 through the projecting needle 55. Because the first operational
stage has
displaced the needle 55 into the skin, the contents of the barrel portion 53
are injected
directly into a subcutaneous region of the patient.
Referring to Figure 6, in one embodiment of the invention, the automatic
injection device 10 may comprise two interlocking components: a syringe
housing
assembly 121 containing the proximal components of the device 10 (e.g., the
syringe
barrel 53, coil spring 89, needle 55 and other proximal components), and a
firing
mechanism assembly 122 containing the distal components of the device (e.g.,
the
means for actuating the syringe). The syringe housing assembly 121 and the
firing
mechanism assembly 122 may be coupled through any suitable means. In the
illustrative embodiment, a proximal end 122a of the firing mechanism assembly
122
may be sized and configured to be inserted into a distal end 12Ib of the
syringe housing
assembly 121. In addition, one or more tabs 127 (shown in detail in Figures 7,
8A-8C,
and 9) on the proximal end 122a of the firing mechanism assembly 122 may snap-
fit into
corresponding openings 126 on the distal end 12Ib of the syringe housing
assembly 122
to ensure alignment and coupling of the two assemblies 121, 122 and the
components
housed therein. =
Figure 7 is an exploded view of the firing mechanism assembly 122 according to
an illustrative embodiment of the invention. As shown, the firing mechanism
assembly
122 includes the illustrative activation button 32, the illustrative actuator
cap 34, an
illustrative distal housing component 12b (firing body) and a coil spring 88
or other
biasing mechanism. The illustrative firing mechanism assembly 122 further
includes a
syringe actuator, illustrated as a syringe actuation component 700, that
extends from the
proximal end 122a of the distal housing component 12b for moving the syringe
50 in a
first stage and actuating the syringe 50 to expel its contents in a second
phase.
Figures 8A-8C illustrate the distal housing component 12b, coil spring 88 and
syringe actuation component 700 when assembled without the activation button
32.
Figure 9 is a perspective view of the distal housing component 12b and Figure
10 is a
perspective-view of the'syringe actuation component 700 according to
illustrative '
embodiments of the invention.
As shown in Figures 1-2 and 7-9, the distal housing component 12b includes a
substantially tubular body, which may include contours 128 to facilitate
gripping of the
device 10 by a user. A step 29 may be formed in a distal region 30 to
facilitate seating
CA 02950817 2016-12-07
29
of the actuator cap 34, as described above. Forward of the step 29, the distal
housing
component 12b has a size and shape configured to be inserted into the distal
end of the
syringe housing 121. Tabs 127 are formed to facilitate coupling and/or locking
of the
two housing components 12a and 12b together. As shown in Figure 9, the tabs
127 may
be formed in a depression 127a on the surface of the proximate end of the
distal housing
component 12b, and may also or alternatively include ribs 127b for guiding the
tabs into
a locking position relative to the proximate housing component 12a. One
skilled in the
art will recognize that any suitable means for coupling the two assemblies
together may
be used and that the invention is not =limited to the illustrative coupling
means.
As shown in Figures 2 and 8C, the distal housing component 126 may include an
anchoring cap 12c coupled to a smaller diameter distal end of the distal
housing
component 12b for anchoring the firing mechanisms for actuating the device 10
to the
distal housing component 12b. The interface of the anchoring cap 12c and the
distal
housing component 12b may form a groove 1234 to facilitate a snap fit of the
activation
button 32 on the distal end of the distal housing component 12b. or may be
joined by
other suitable joining means as described above.
Referring to Figures 3 and 10, the syringe actuation component 700 is
preferably
an integrated component formed of any suitable material, such as an acetal-
based plastic,
though other suitable materials may also be used. The syringe actuation
component 700
cOmprises a pressurizing=end 754 for applying pressure to the bung 54 of a =
corresponding syringe 50; a plunger 70 with a compressible expanded '
central portion, illustrated as the plunger elbows 78, as well as other
components, such
as components for anchoring the coil spring 88 to the syringe actuation
component 700,
as described below. The compressible expanded central portion 76 facilitates
movement
of a corresponding syringe 50 into a protracted position and expulsion of the
contents of
the syringe 50 in two separate steps, as described above. Alternatively, the
syringe
actuator may comprise multiple actuators for moving and/or promoting expulsion
of the
syringe 50.
The syringe actuation component 700 of Figures 3 and 10 further may include an
indicator 190 in a solid rod portion 71 of the plunger 70 distal from the
elbows 78. During
operation of the device 10 and after completion of an injection, the indicator
190 is configured
to align with the window 130 on the housing 12 to indicate completion of the
injection.
=
CA 02950817 2016-12-07
The indicator 190 preferably has a distinctive color or design to represent
completion of
an injection.
As shown in Figures 2, 7, 8C and 10, the illustrative syringe actuation
component 700 further includes a retaining flange 720 for holding the
actuating coil
5 spring 88 in a compressed position until actuation. The retaining flange
720 is sized,
dimensioned and formed of a material that preferably allows the syringe
actuation
component 700 to slidably and easily move within the housing 12 when the
device 10 is
actuated. Extending distally from the retaining flange 720, the syringe
actuation
component 700 forms a base 788 for the actuating coil spring 88. The base 788
10 terminates in a trigger anchoring portion 789. The illustrative base 788
may comprise
flexible legs 788a, 788b around which the spring 88 coils. The trigger
anchoring portion
. 789 may comprise tabbed feet 7891 extending from the base 788 and configured
to -
selectively engage the anchoring cap 12c and/or distal housing component 12b.
The
activation button 32 coupled to the distal end of the distal housing component
12b is
15 configured to hold the trigger anchoring portion 789 until activation.
When activated,
the activation button 32 releases the trigger anchoring portion 789, allowing
the coil
spring 88 to propel the syringe actuation component 700 towards the proximal
end 20 of
the device 10 in an operation described above.
In a retracted, anchored position shown Figure 2, 8C and 10 (corresponding to
20 the schematic of Figure 3), the trigger anchoring portion 789 interacts
with the housing
12, which holds the tabbed feet 7891in a latched position, against the biasing
force of the
coil.spring 88, to maintain the syringe actuation component 700 in a retracted
position.
In this position, the flange 720 retracts the spring 88 against the back,
distal wall 712 of
the distal housing component 12b. An opening 713 in the anchoring cap 12c
allows the
25 activation button 32 access to the Anchoring'portion 789. Intheletracted
position, the
pressurizer 754 of the syringe actuation component 700 extends out of an
opening 228
on the proximal end 122a of the distal housing component 12b. When the distal
housing
component 12b couples to a corresponding syringe actuation mechanism 121, the
pressurizer 754 extends into the barrel portion of a syringe housed therein.
The
30 pressurizer 754 may be integral with, the same as, connected to, or
otherwise in
communication with the bung 54 of a syringe 50 housed in the device 10 and may
have
any suitable size, shape and configuration suitable for applying pressure to
the bung 54.
In one embodiment, the pressurizer 754 has a cross-section corresponding to
the shape
CA 02950817 2016-12-07
31
of the barrel portion 53 of a corresponding syringe 50 so as to substantially
seal the
barrel portion 53, and.the pressurizer 754 is configured to slidably move
within the
barrelportion 53 to apply pressure to the bung 54 and actuate the syringe 50.
=
In the illustrative embodiment of Figures 7-10, the syringe actuation
component
700 constitutes a single, integrated mechanism for anchoring a corresponding
syringe
50, spring 88 and other components, actuating and moving the syringe 50 to a
protracted
position, and separately expelling the contents of the syringe 50.
Figure 11 is an exploded view of the syringe housing assembly 121 of an
illustrative embodiment of the invention, which is configured to couple to and
interact
with the firing mechanism assembly 122 of Figures 7-10. The illustrative
syringe
housing assembly 121 includes a proximal housing component 12a, the proximate
cap
24, a proximal, second biasing mechanism 89, a syringe carrier 500 and a
stepped
shroud 12d forming a proximate portion 20 of the housing 12 when assembled and
includes the proximate opening 28, as also shown in Figure 2. The components
12a,
12d, 89, 500 and 24 cooperate to house a syringe 50 containing a substance to
be
injected and facilitate operation of the device. 10 in=the two different
operational stages
as described above. ' =
Illustrative embodiments of the syringe carrier 500, the stepped shroud I2d
and
the proximate cap 24 are shown in detail in Figures 12, 13 and 14,
respectively. Figures
15a and 15b are a perspective side view and a cross-sectional side view,
respectively, of
the assembled spring housing assembly 121 according to one embodiment of the
invention. One skilled in the art will recognize that the invention is not
limited to the
illustrative embodiments.
Referring now to Figures 1,2, 11, 12 and 15b, the syringe carrier 500 of the
illustrative embodiment envelopes the distal half of a syringe 50 used in the
device 10.
The syringe 50 rests in the carrier 500, and both are contained in the housing
12. During
operation, the syringe 50 and carrier 500 move forward (e.g., proximally)
within the
housing 12. The housing 12 stops and limits the movement of the carrier 500,
and the
cariier 500 iti.turn stops and. limits the movement'of the syringe 50. The
illustrative
syringe carrier 500 has a substantially tubular structure including window
cutouts 501
preferably aligned with the window 130 on the housing 12a to allow a user to
view the
contents of the syringe 50 prior to operation. The syringe carrier 500 may
include a
flanged distal end 562 configured to interface with a flanged distal end 56
(shown in
CA 02950817 2016-12-07
32
Figures 3 and 15b) of the syringe 50. The flanged distal end 562 may serve as
a damper
for the syringe 50. The syringe carrier 500 may further include an
intermediate flange
563, which in the illustrative embodiment forms a stop for the syringe 50 that
interacts
with an interior stop 256 (shown in Figure 15b) on the proximate housing
component
12a to limit forward motion of the syringe 50. The illustrative syringe
carrier 500 may
further include a proximate anchor portion 503 that limits movement of the
syringe 50 in
a distal,.rearward direction. In the illustrative embodiment, the proximate
anchor
portion 503 includes a radial groove configured to engage the interior stop
256. A
syringe carrier coupler 504 extends forward past the proximate anchor portion
503 to
facilitate coupling of the syringe carrier 500 with the distal end of the
spring 89 and the
stepped shroud 12d, as shown in Figure 15b. In one embodiment, the syringe
carrier
500 is stationary within the housing 12 and the syringe 50 selectively and
controllably
slides within and relative to the syringe carrier 500. Alternatively, the
syringe carrier
500 is slidably disposed within the housing 12 and selectively carries the
syringe 50
within the housing 12. The syringe carrier 500 may have any suitable
configuration and.
size suitable for carrying or guiding the syringe 50 within the housing 12.
Referring to Figures 13 and 15b, the illustrative stepped shroud 12d forms a
proximate end 20 of the housing 12. The illustrative stepped shroud 12d has a
substantially tubular body, including a proximate boss 112 defining the
proximate
opening 28 of the device 10, through which the syringe needle 55 projects
during
Operation Of the device 10. A step 113 from the main tubular body portion 116
forms
the proximate boss 112 of smaller diameter than the main tubular body portion
116 of
the stepped shroud 12d. As shown in Figure 15b, the step 113 forms a forward
stop for
the spring 89 to confine the spring 89 and prevent forward movement of the
spring
89towards the proximate end 20 of the device 10. In the illustrative
embodiment, shown
in Figure 15b, the distal rim 115 of the stepped shroud 12d abuts the
proximate side of
the stop 256 of the proximal housing component 12a. Referring now to Figure
13, distal
arms 114 extend from the stepped shroud I2d to lock in the stepped shroud 12d
to
prevent accidental needle sticks.
Referring to Figures 14, 15a and 15b, the interior of the illustrative cap 24
may
include a plurality of radial grooves 241, 243 for receiving protruding
portions of the
stepped shroud 12d and the proximal housing component 12a. For example, as
best
illustrated in Figure 15b, a first radially outer groove 241 receives a
proximate end of the
CA 02950817 2016-12-07
33
sidewall 242 of the proximal housing component I2a. A second, radially inner
groove
243 receives the proximate end of the boss 112. The cap boss 26 extends into
the inner
lumen 1012 of the housing 12 and surround the proximal end of a syringe 50
loaded
therein when the cap 24 is coupled to the housing 12. In an embodiment, an
interior
needle cover 246 (shown in Figure 15b) of the cap 24 sheaths the syringe
needle 55.
When the cap 24 is removed, the syringe needle 55 is exposed within the lumen
1012 of
the housing 12. The cap 24 may also include an opening in a proximal end 248
thereof.
As described above and shown in Figure 15a, openings 126 in the proximal
housing component 12a receive tabs 127 Of the firing mechanism assembly 122 to
facilitate assembly of the device 10. The window 130 described above for
allowing a
user to view the contents of a syringe contained in the assembly 121, as well
as to view
an indicator 190 that fills the window 139 after completion of an injection
may be. =
formed in the proximal housing component 12a.
Figures 16A and 16B are cross-sectional views at 90 degree offset angles from
each other, illustrating an assembled automatic injection device 10, wherein
the syringe
housing assembly 121 and a firing mechanism assembly 122 are coupled together,
such
that the pressurizer 754 of the syringe actuation component 700 extends into
the barrel
portion 53 of a syringe 50 housed in the syringe housing assembly 121 and in
communication with a bung 54 of the syringe 50.
As shown, in Figure 16b the trigger anchoring portion 789 of the syringe
actuation component 700 is anchored towards the distal end of the housing 12
by the
activation button 32. When a user depresses the activation button 32, driving
arms 32a
connected to the activation button 32 compress the tabbed feet 7891 of the
trigger
anchoring portion 789, releasing the syringe actuation mechanism 700 and
releasing the
spring 88. Prior to operation, the compressible expanded central portion 76,
illustrated
as elbows 78, of the syringe actuation component 700 rests above the flange 56
of the
syringe 50 to allow the compressible expanded central portion 76, when pushed
by a
released coil spring 88, to apply pressure to the syringe barrel portion 53,
thereby
moving the syringe 50 forward within the housing 12 when actuated. As
described
above, once a stop, such as a stop 256 on the proximal housing component 12a
shown in
Figure 15b and Figure 16a, catches the syringe and halts additional forward
motion of
the projecting syringe 50, the continued biasing force on the spring 88 will
continue to
move the syringe actuation component 700 forward, causing the compressible
expanded
CA 02950817 2016-12-07
34
central portion 76 to compress and move into the barrel portion 53 of the
syringe 50.
The forward motion of the syringe actuation component 700 within the barrel
portion 53
. -
causes the pressurizer 754 to apply pressure to the bung 54, causing expulsion
of the
syringe contents into an injection site.
As also shown in Figures 16a and 16b, the actuator cap 34 may include a
stabilizing protrusion 340 that extends through the activator button 32 and
between the
feet tabbed 7891 of the syringe actuation component 700 to stabilize the
components of
the device prior to activation.
Figure 17 is a detailed view of the interface between a syringe housing
assembly
121 and a firing mechanism assembly 122 (referring to Figures 6 and 8a) of an
automatic injection device 10 of an embodiment of the invention, illustrating
the
indicator 190 of the syringe actuation component 700 according to one
embodiment of
the invention. The indicator 190 may have a distinctive color and/or design to
indicate
to a user that an injection is complete. Also referring to Figure 2, the
indicator 190 is
configured to align with the window 130 of the housing 12 after the syringe
actuation
component 700, with the compressible expanded central portion 76 collapsed and
moved
forward within the barrel portion 53, completes an injection and fully or
substantially
fully expels the contents of the syringe 50 out of the needle 55 and into a
patient. Thus,
prior to operation of the device 10, the syringe barrel 53 aligns with the
window 130 and
the contents are viewable therein. After injection, with the syringe barrel
portion 53 has
moved towards the proximal end 20 of the device 10, such that the needle 55
protrudes
from the proximal end 20 into an injection site, and the syringe actuation
component 700
has moved forward within the syringe barrel portion 53, the indicator 190
aligns with the
window 130 to indicate completion of an injection. Therefore, even if the
first stage of
operation (movement of the syringe 50 into an exposed position with the needle
55
protruding) is complete, the indicator 190 will not align with the window 130
or
otherwise indicate completion of an injection until the syringe actuation
component 700
has pushed the contents of the syringe 50 out of the barrel 53.
Figures 18-22 are cross-sectional views of an assembled automatic injection
device 10' according to an illustrative embodiment of the invention. The
illustrative
embodiment of the automatic injection device 10' includes two mating proximal
and
distal housing components I 2a, 12b. The proximal and distal housing
components 12a,
12b mate to form a complete housing 12. As shown, a proximal housing component
CA 02950817 2016-12-07
12a, forming a proximal end of the housing 12, receives a proximal end of the
distal
housing components 126. A cooperating projection 312 and groove 313, or a
plurality
of cooperating projections 312 and grooves 313, facilitate mating of the
proximal and
distal housing components 12a, 12b in the illustrative embodiment. Other
suitable
5 mating mechanisms may alternatively be employed. A shelf 29 formed on an
outer
surface of the distal housing component 12b may form a stop for the second
removable
cap 34.
As shown, the activation button 32' may be a 'cap ebirering the distal end of
the
distal housing component 12b. The illustrative activation button 32' slides
relative to
10 the distal housing component 12b to actuate a syringe actuator, such as
the plunger 70 or
syringe actuation component 700. A shelf/step 138 formed on the outer surface
of the
distal housing component 12b near the distal end 30 of the distal housing
component
12b allows for and limits the movement of the activation button 32' relative
to the
housing 12, as shown in Figures 20 and 22. The illustrative activation button
32'
15 releasably retains flexible anchoring arms 172 of the plunger 70'. When
depressed, the
activation button 32' releases the flexible anchoring arms 172 to allow a
first biasing
mechanism, illustrated as spring 88' to propel the plunger 70' towards the
proximal end
of the device 10'.
In the embodiment of Figures 18-22, the plunger 70' further includes a flange
20 72' located between the compressible extended middle portion 78 and the
distal end of
the plunger rod 71'. A first biasing mechanism 88' is seated between an
interior distal
end of the housing 12 and the flange 72' to bias the plunger 70 towards the
proximal end
of the housing 12'. As described above, when the activation button 34'
releases the
anchoring arms 172, the coil spring 88', or other suitable biasing mechanism
propels the
25 plunger 70' towards the proximal end 20 of the device 10.
The illustrative embodiment 10' further includes an indicator 190 formed at an
intermediate portion of the plunger rod 71' between the flange 72' and the
compressible
extended portion 76, illustrated as flexible elbows 78'.
The syringe 50' of Figures 18-22 may include protrusions or other suitable
30 component to facilitate controlled movement of the syringe within the
housing 12'. For
example, with reference to Figure 18, the syringe 50' includes a sleeve 157
forming a
proximal protrusion 158 for abutting a proximal side of a first protrusion 168
formed on
an inner surface of the housing 12' for limited movement of the syringe50' in
the distal
CA 02950817 2016-12-07
36
direction within the housing 12'. The sleeve 157 may also form a flange 159
that may
abut the distal side of the first protrusion 168 to limit movement of the
syringe 50' in the
proximal direction during an injection.
In the embodiment of Figures 18-22, the second biasing mechanism, illustrated
as coil spring 89' is disposed about a proximal portion of the syringe 50'. A
shelf 169
formed at a proximal inner surface of the housing 12' receives a proximal end
of the coil
spring 89'. Referring to Figure 19, the proximal protrusion 158 of the syringe
sleeve
157, or another suitably disposed mechanism, receives the distal end of the
coil spring
89'. As described above, the second biasing mechanism 89' biases the syringe
50' in a
retracted position within the housing 12' until activation of the device 10.
As shown in Figures 18-22, the automatic injection device 10' incorporates an
indicator 190 to indicate' to the user of the device 10 when the dose from the
syringe 50
has been fully or substantially fully ejected. In the illustrative embodiment,
the indicator
190 is formed on a portion of the plunger rod 71' between the compressible
expanded
central portion 76 and the flange 72'. As the plunger rod 71 moves during
operation, the
indicator 190 advances towards and aligns with window 130 as the dose empties
from
the syringe. The indicator 190, which is preferably a different color or
pattern from the
substance being injected, fills the window 130 entirely to indicate that the
dosage has
been ejected. Any suitable indicator may be used.
After injection of the dose from the device 10 via the needle 55, a needle
sheath
112, which may be formed by the proximal end 20 of the shroud 12d may
automatically
advance over the exposed needle 55 extending from the housing proximal end 20
to
prevent accidental sticks.
Referring to Figure 23, the illustrative housing 12 includes a window 130
formed
=
through a side wall of the housing 12 to allow a user to view the contents of
the syringe.
The illustrative window 130 preferably has a keyhole shape. For example, the
window 130 includes a first end 132 that is substantially linear, and may
include a
curved inner edge 132a. The second end 134 of the window 130 may be
substantially
hemispherical in shape and wider than the first end 132 of the window 130. The
window 130 may include a fill line 135 to allow verification of the proper
dosage within
the syringe.
According to one embodiment of the invention, the illustrative automatic
injection device may be used to deliver a dose of a TNF inhibitor used to
treat arthritis
CA 02950817 2016-12-07
37
and other diseases. In one embodiment, the solution contained in the syringe
50 or 50'
contains 40 milligrams of drug product (TNFct blocker or inhibitor), 1 mL of
adalimumab: 40 mg adalimurnab, 4.93 ing sodium chloride, 0;69 mg monobasic
sodium
phosphate dehydrate, 1.22 mg dibasic sOdium'phosphate dehydrate, 0.24 mg
sodium
citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate
50 and
water for injection, with USP sodium hydroxide added as necessary to adjust pH
to be
about 5.2.
Figure 24 illustrates use of the device to deliver a dosage of a substance,
such as
a TNF inhibitor, to a subcutaneous region of a user according to an
illustrative
embodiment of the invention. In a first step, a pre-loaded automatic injection
device,
such as the device 10 or device 10' described above, is provided to a user.
Next, the
user selects and prepares an injection site 400 for receiving the substance in
a
subcutaneous region. For example, the user may clean the injection site using
a suitable
cleaning device, such as an alcohol preparation pad, which may be integrated
with the
device 10 or 10' of the present invention. Following the preparation, the user
prepares
the dose for injection. For example, the user may examine the solution through
the
window 130 to ensure that the solution has a proper color and consistency and
that the
level of the liquid is at the fill line to ensure proper dosage. After
ensuring proper
dosage and contents in the pre-filled syringe 50, the user then removes the
first cap 24
and second cap 34 of the device 10 or 10' to expose the opening 28 on the
first end 20
and the activation button 32 on the second end 30. Then, the user places the
automatic
injection device 10 or 10' with the open first end 20 adjacent or proximal to
the injection
site. The user may squeeze the skin in this area to facilitate injection. The
automatic
injection device 10 or 10' is preferably held at about a ninety-degree angle
to the body
. of the user, flush against the skin, as shown in Figure 24. After placement,
the user
presses the activation button 32 to initiate an injection. The depression of
the activation
button may effect an audible indicator (noise), such as a "click" to indicate
initiation of
the injection. As described above, depression of the activation button 32
causes the
a.ctivation button to release the anchor, such as the anchor end 789 of the
syringe
actuation component 700, allowing a biasing spring 88 to propel the syringe
actuation
component 100, and thus, the syringe 50 towards the proximal end 20 of the
device 10
or 10'. After the syringe 50 pierces the skin, or otherwise enters an
administration site,
the syringe 50 forward movement stops, which the syringe actuator mechanism,
or other
CA 02950817 2016-12-07
38
mechanism, then pushes on the syringe bung 54 to expel the contents of the
syringe 50.
The user maintains the automatic injection device 10 or 10' in the position
shown in
Figure 24 for a predetermined time period. If an indicator 190 is provided in
the
automatic injection device 10, the user maintains the automatic injector
device 10 in
position until the indicator 190 fills the window 130 indicating that a full
or substantially
full dose of the substance has been injected. Afterwards, the user removes the
device
100 to pull the needle 55 out of the skin. The needle.55.is preferably
automatically
sheathed to prevenraccidental pricks. The user may then dispose of the empty'
automatic injection device 10 or 10'.
According to anotherembodiment of the invention, a training automatic
injection
device may be provided for training users how to use the automatic injection
device 10
or 10'. The illustrative training injection device mimics the functionality of
the
automatic training device 10 or 10' without injecting a substance into a
patient. The
training automatic injection device may have substantially similar components
as the
automatic injection devices 10, 10' described above, yet lacks a needle and/or
a drug.
For example, the training automatic injection device may be filled with air
that is
expelled from the syringe barrel portion 53 when activated. The operation of
the
training automatic injection device advances the syringe and expels the air or
other
benign substance, preferably without penetrating the skin of the user. The
training
automatic injection device preferably includes an indicator., such as
indicator 190: The
training Automatic injection device may help train user to become accustomed
to toe
handling, sound, feel, operation, use of the indicator 190 and/or timing of
the automatic
injection device without wasting valuable resources.
The present invention provides significant advantages over prior methods for
administering drugs, particularly TNFa inhibitors. For example, the automatic
injection
device enhances administration, convenience, is less painful, includes a
hidden needle to
remove apprehension and anxiety for patients who are "needle phobic" to one
degree or
another so that fear is not a factor. In addition, the automatic injection
device efficiently
delivers a drug or other substance while being safe. The automatic injection
device of
the invention also offers safety advantages. Unlike traditional syringes,
there is no
needle exposure with the automatic injection device. The automatic injection
device
contains a white needle sleeve that surrounds the needle and protects patients
from
needlestick injury before and after use. Also, a safety cap on the automatic
injection
CA 02950817 2016-12-07
39
device prevents accidental misfiring, a potential occurrence with prefilled
syringes. An
audible "click" announces the beginning of the injection, and a distinctive
indicator in
the inspection window shows the patient that the complete dose was fully
administered.
Examples of uses of the automatic injection device of the invention also are
described in detail in PCT/EP2005/002487. U.S. Design Patent No. D622374 and
D629509 also describe automatic injection devices.
DT. TNFa Inhbitors For Use in Compositions and Methods of Invention
The present invention can be used to administer a dose of a substance, such as
a
liquid drug, e.g., a TNFa. inhibitor, to a user (also referred to herein as a
patient). In one
embodiment, the dose delivered by the automatic injection device of the
invention
comprises a human TNFa antibody, or antigen-binding portion thereof. A
particularly
preferred medication is a TNFa inhibitor.
The term "human TNFa" (abbreviated herein as hTNFa., or simply hTNF), as
used herein, is intended to refer to a human cytokine that exists as a 17 kD
secreted form
and .a 26 kD membrane associated form, the biologically active form of which
is
composed of a trimer of noncovalently bound 17 kD molecules. The structure of
hTNFa is described further in, for example, Pennica, D., et al. (1984) Nature
312:724-
729; Davis, J.M., eral. (1987) Biochemistry 2.6:1322-1326; and Jones, E.Y.,
etal. (1989)
Nature 338:225-228. The term human TNFa is intended to include recombinant
human
TNFa (rWITIFcc), which can be prepared by standard recombinant expression
methods
or put-Chased commercially (R & D Systems, Catalog No. 210-TA, Minneapolis,
MN).
TNFa is also referred to as TNF.
The term "TNFa inhibitor" refers to an agent that interferes with TNFa
activity.
The term also includes each of the anti-TNFcx human antibodies (used
interchangeably
herein with TNFa antibodies) and antibody portions described herein as well as
those
described in U.S. Patent Nos. 6,090,382; 6,258,562; 6,509,015, and in U.S.
Patent
No. 7,223,394 and U.S. Patent Application Publication No. 2003/0219438. In one
embodiment,
the TNFcc
inhibitor used in the invention is an anti-TNFa antibody, or a fragment
thereof,
CA 02950817 2016-12-07
including infliximab (Remicade , Johnson and Johnson; described in U.S. Patent
No.
5,656,272), CDP571 (a humanized monoclonal anti-
TNF-alpha IgG4 antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha
antibody fragment), an anti-TNF dAb (Peptech), CNTO 148 (golimumab; Medarex
and
5 Centocor, see WO 02/12502), and adalimumab (HUMIR.Ae Abbott Laboratories,
a
human anti-TNF mAb, described in US 6,090,382 as D2E7). Additional TNF
antibodies
that may be used in the invention are described in U.S. Patent Nos. 6,593,458;
6,498,237; 6,451,983; and 6,448:380.
In another embodiment, the TNFa inhibitor is a -INF fusion protein, e.g.,
etanercept
10 (Enbrele, Amgen; described in WO 91/03553 and WO 09/406476),
In another embodiment, the TNFa inhibitor is a recombinant 'INF
binding protein (r-TBP-I) (Serono).
The term "antibody", as used herein, is intended to refer to immunoglobulin
molecules comprised of four polypeptide chains, two heavy (H) chains and two
light (L)
15 chains inter-connected by disulfide bonds. Each heavy chain is comprised
of a heavy
chain variable region (abbreviated herein as HCVR or VH) and a heavy chain
constant
region. The heavy chain constant region is comprised of three domains, CHI,
CH2 and
CH3.Each light chain is comprised of a light chain variable region
(abbreviated herein
as LCVR or VL) and a light chain constant region. The light chain constant
region is
20 comprised of one domain, CL. The VH and VL regions can be further
subdivided into
regions of hypervariability, termed complementarity determining regions (CDR),
interspersed with regions that are more conserved, termed framework regions
(FR).
Each VH and VL is composed of three CDRs and four FRs, arranged from amino-
terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2,
FR3,
25 CDR3, FR4. The antibodies of the invention are described in further
detail in U.S. Patent
Nos. 6,090,382; 6,258,562; and 6,509,015),
The term "antigen-binding portion" of an antibody (or simply "antibody
portion"), as used herein, refers to one or more fragments of an antibody that
retain the
30 ability to specifically bind to an antigen (e. g. , hTNFoc). It has been
shown that
fragments of a full-length antibody can perform the antigen-binding function
of an
antibody. Examples of binding fragments encompassed within the term "antigen-
binding portion" of an antibody include (i) a Fab fragment, a monovalent
fragment
CA 02950817 2016-12-07
41
consisting of the VL, VH, CL and CHI domains; (ii) a F(ab1)2 fragment, a
bivalent
fragment comprising two Fab fragments linked by a disulfide bridge at the
hinge region;
64 a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment
consisting
of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment
(Ward et
al. (1989) Nature 4j.:544-546),3 which consists of a VH or VL domain; (vi)
an isolated
complementarity determining region (CDR); and (vii) a dual variable domain
(DVD)
antibody. Furthermore, although the two domains of the Fv fragment, VL and VH,
are
coded for by separate genes, they can be joined, using recombinant methods, by
a
synthetic linker that enables them to be made as a single -Protein chain in
which the VL
and VH regions pair to form monovalent molecules (known as single chain Fv
(scFv);
see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988)
Proc. Natl.
Acad. Sci. USA :5879-5883).85 Such single chain antibodies are also
encompassed
within the term "antigen-binding portion" of an antibody. Other forms of
single chain
antibodies, such as diabodies are also encompassed. Diabodies are bivalent,
bispecific
antibodies in which VH and VL domains are expressed on a single polypeptide
chain,
but using a linker that is too short to allow for pairing between the two
domains on the
same chain, thereby forcing the domains to pair with complementary domains of
another
chain and creating two antigen binding sites (see e.g., Holliger etal. (1993)
Proc. Natl.
Acad. ScL USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123). The
antibody portions of the invention are described in further detail in U.S.
Patent Nos.
6,090,382, 6,258,562, 6,509,015),
In one embodiment, the TNF inhibitor used in the methods=and compositions of
the invention includes a TNF fusion protein, e.g., ctanercept (Enbrel , Amgen;
described
in WO 91/03553 and WO 09/406476.), as well as a
recombinant TNF binding protein (r-TBP-I) (Serono).
In one embodiment, the TNF inhibitor used in the methods and compositions of
the invention includes isolated human antibodies, or antigen-binding portions
thereof,
that bind to human INFct with high affinity and a low off rate, and have a
high
neutralizing capacity. Preferably, the human antibodies of the invention are
recombinant, neutralizing human anti-hTNFa antibodies_ The most preferred
recombinant, neutralizing antibody of the invention is referred to herein as
D2E7, also
referred to as HUMIRA. or adalimuinab (the amino acid sequence of the D2E7 VL
CA 02950817 2016-12-07
42
region is shown in SEQ ID NO: 1 of US patent 6,090,382 the amino acid sequence
of
theD2E7 VII region is shown in SEQ ID NO: 2 of US patent 6,090,382). The
properties of 1D2E7 (HIJMIRA. ) have been described in Salfeld et al., U.S.
Patent Nos.
6,090,382, 6,258,562, and 6,509,015.
Other examples of-INF . inhibitors include chimeric and humanized murine anti-
hTNFa antibodies that have undergone clinical testing for treatment of
rheumatoid
arthritis (see e.g., Elliott et at. (1994) Lancet 344:1125-1127; Elliot et al.
(1994) Lancet
344:1105-1110; Rankin el al. (1995) Br. J. RheumatoL 34:334-342). In another
embodiment, the TNFa inhibitor used in the invention is an anti-TNFa antibody,
or a
fragment thereof, comprising infliximab (Remicade, Johnson and Johnson;
described in
U.S. Patent No. 5,656,272), CDP571 (a humanized
monoclonal anti-TNF-alpha Ig04 antibody), CDP 870 (a humanized monoclonal anti-
TNF-alpha antibody fragment), an anti-TNF dAb (Peptech), and CNTO 148
(golimumab; Medarex and Centocor, see WO 02/12502).
The term "recombinant human antibody", as used herein, is intended to include
all human antibodies that are prepared, expressed, created or isolated by
recombinant
means, such as antibodies expressed using a recombinant expression vector
transfected
into a host cell (described further below), antibodies isolated from a
recombinant,
combinatorial human antibody library (described further below), antibodies
isolated
from an animal (e.g., a mouse) that is transgenic for human immunoglobulin
genes (see
e.g., Taylor et al. (1992) NucL Adds Res. 20:6287) or antibodies prepared,
expressed,
created or isolated by any other means that involves splicing of human
immunoglobulin
gene sequences to other DNA sequences. Such recombinant human antibodies have
variable and constant regions derived from human germ line inununoglobulin
sequences.
In certain embodiments, however, such recombinant human- antibodies are
subjected to
in vitro mutagenesis (or; when an animal transgenic for human 1g sequences is
used, in
vivo somatic mutagenesis) and thus the amino acid sequences of the VU and VL
regions
of the recombinant antibodies are sequences that, while derived from and
related to
human germ line VH and VL sequences, may not naturally exist within the human
antibody germ line repertoire in vivo.
Such chimeric, humanized, human, and dual specific antibodies can be produced
by recombinant DNA techniques known in the art, for example using methods
described
in PCT International Application No. PCTTUS86/02269; European Patent
Application
CA 02950817 2016-12-07
43
No. 184,187; European Patent Application No. 171,496; European Patent
Application
No. 173,494; PCT International Publication No. WO 86/01533; U.S. Pat. No.
4,816,567;
European Patent Application No. 125,023; Better etal. (1988) Science 240:1041-
1043;
Liu etal. (1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu eral. (1987)J.
lmmunol.
139:3521-3526; Sun etal. (1987) Proc. Natl. Acad. Sci. USA 84:214-218;
Nishimura et
al. (1987) Cancer Res. 47:999-1005; Wood etal. (1985) Nature 314:446-449; Shaw
et
al. (1988) J. Natl. Cancer Inst. 80:1553-1559; Morrison (1985) Science
229:1202- 1207;
Oi etal. (1986) BioTechniques 4:214; U.S. Pat. No. 5,225,539; Jones etal.
(1986)
Nature 321:552-525; Verhoeyan etal. (1988) Science 239:1534; and Beidler etal.
(1988)J. Immunol. 141:4053-4060, Queen etal., Proc. Natl. Acad Sci. USA
86:10029-
10033 (1989), US 5,530,101, US 5,585,089, US 5,693,761, US 5,693,762, Selick
etal.,
WO 90/07861, and Winter, US 5,225,539.
An "isolated antibody", as used herein, is intended to refer to an antibody
that is
substantially free of other antibodies having different antigenic
specificities (e.g., an
isolated antibody that specifically binds hTNFa is substantially free of
antibodies that
specifically_bind antigens other than hTNFa). An isolated antibody that
specifically
binds hTNFa may, however, have cross-reactivity to other antigens, such as
TNFa
molecules from other species. Moreover, an isolated antibody may be
substantially free
of other cellular material and/or chemicals.
A "neutralizing antibody", as used herein (or an "antibody that neutralized
hTNFa activity"), is intended to refer to an antibody whose binding to hTNFa
results in
inhibition of the biological activity of hTNFa. This inhibition of the
biological activity
= of hTNFor_ can be assessed by measuring one or more indicators of hTNFa
biological
activity, such as hTNFa-induced cytotoxicity (either in vitro or in vivo),
hTNFa-induced
cellular activation and hTNFa binding to hTNFa receptors. These indicators of
hil.s1Fa
biological activity can be assessed by one or more of several standard in
vitro or in vivo
assays known in the art (see U.S. Patent No. 6,090,382). Preferably, the
ability of an
antibody to neutralize hTNFa activity is assessed by inhibition of hTNFa-
induced
cytotoxicity of L929 cells. As an additional or alternative parameter of
hTNFot. activity,
the ability of an antibody to inhibit hTNFa-induced expression of ELAM-I on
HUVEC,
as a measure of hTNFa-induced cellular activation, can be assessed.
The term "surface plasmon resonance", as used herein, refers to an optical
phenomenon that allows for the analysis of real-time biospecific interactions
by
CA 02950817 2016-12-07
44 '
detection of alterations in protein concentrations within a biosensor matrix,
for example
using the BlAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and
Piscataway,
NJ). For further descriptions, see Example I of U.S. Patent 6,258,562 and
Jonsson etal.
(1993)Ann. Biol. Clin. 51:19; JOnsson et al. (1991) Biotechniques 11:620-627;
Johnsson
etal. (1995) J. Mot. Recognit. 8:125; and Johnnson etal. (1991)
AnaLBiochem.198:268.
The term "Koff', as used herein, is intended to refer to the off rate constant
for
dissociation of an antibody from the antibody/antigen complex.
The term "Kd", as used herein, is intended to refer to the dissociation
constant of
a particular antibody-antigen interaction.
The term "IC50" as used herein, is intended to refer to the concentration of
the
inhibitor required to inhibit the biological endpoint of interest, e.g.,
neutralize
cytotoxicity activity.
= The term "dose," as used herein, refers to an amount of a substance, such
as a
TNFa inhibitor, which is administered to a user preferably using the automatic
injection
device of the invention. In one embodiment, the dose comprises an effective
amount,
for example, including 20 mg, 40 mg, 80 mg, and 160 mg, of the TNFa inhibitor
adalimumab.
The term "dosing", as used herein, refers to the administration of a substance
(e.g., an anti-TNFa antibody) to achieve a therapeutic objective (e.g.,
treatment of
rheumatoid arthritis).
A "dosing regimen" describes a treatment schedule for a substance, such as a
TNFa inhibitor, e.g., a treatment schedule over a prolonged period of time
and/or
throughout the course of treatment, e.g. administering a first dose of a INFoc
inhibitor at
week 0 followed by a second dose of a TNFa inhibitor on a biweekly dosing
regimen.
The terms "biweekly dosing regimen", "biweekly dosing", and "biweekly
administration", as used herein, refer to the time course of administering a
substance
(e.g., an anti-TNFa antibody) to a patient to achieve a therapeutic objective,
e.g.,
throughout the course of treatment. The biweekly dosing regimen is not
intended to
include a weekly dosing regimen. Preferably, the substance is administered
every 9-19
days, more preferably, every 11-17 days, even more preferably, every 13-15
days, and
most preferably, every 14 days. In one embodiment, the biweekly dosing regimen
is
initiated in a patient at week 0 of treatment. In another embodiment, a
maintenance dose
is administered on a biweekly dosing regimen. In one embodiment, both the
loading and
CA 02950817 2016-12-07
Maintenance doses are administered according to a biweekly dosing regimen. In
one
embodiment, biweekly dosing includes a dosing regimen wherein doses of a
TNFa inhibitor are administered to a patient every other week beginning at
week 0. In
one embodiment, biweekly dosing includes a dosing regimen where doses of a
5 TNFoc inhibitor are administered to a patient every other week
consecutively for a given
time period, e.g., 4 weeks, 8 weeks, 16, weeks, 24 weeks, 26 weeks, 32 weeks,
36
. .
weeks, 42 weeks, 48 weeks, 52 weeks; 56 weeks, etc. biweekly dosing methods
are also
described in US 20030235585.
The term "combination" as in the phrase "a first agent in combination with a
10 second agent" includes co-administration of a first agent and a second
agent, which for
example may be dissolved or intermixed in the same pharmaceutically acceptable
carrier, or administration of a first agent, followed by the second agent, Or
administration
of the second agent, followed by the first agent.
The term "concomitant" as in the phrase "concomitant therapeutic treatment"
15 includes administering an agent in the presence of a second agent. A
concomitant
therapeutic treatment method includes methods in which the first, second,
third, or
additional substances are co-administered. A concomitant therapeutic treatment
method
also includes methods in which the first or additional agents are administered
in the
presence of a second or additional substances, wherein the second or
additional agents,
20 for example, may have been previously administered. A concomitant
therapeutic'
treatment method may be executed step-wise by different patients. For example,
one
subject may administer to a user a first agent and a second subject may to
administered
to the user a second substance, and the administering steps may be executed at
the same
time, or nearly the same time, or at distant times, so long as the first
substance (and
25 additional substances) are after administration in the presence of the
second substance
(and additional substances). The actor and the user may be the same entity
(e.g.,
human).
The term "combination therapy", as used herein, refers to the administration
of
two or more therapeutic substances, e.g., an anti-TNFa antibody and another
drug. The
30 other drug(s) may be administered concomitant with, prior to, or
following the
administration of an anti-TNFcc antibody.
The term "treatment," as used within the context of the present invention, is
meant to include therapeutic treatment, as well as prophylactic or suppressive
measures,
CA 02950817 2016-12-07
46
for the treatment of a disorder, such as a disorder in which TNFa is
detrimental, e.g.,
rheumatoid arthritis.
In one embodiment, the invention provides improved uses and compositions for
treating a disorder in which TNFa is detrimental, e.g., rheumatoid arthritis
with a TNFa
inhibitor, e.g., a human TNFa antibody, or an antigen-binding portion thereof,
through
an automatic injection device.
The substance that is delivered via the automatic injection device of the
invsntion may 12e a TNFa. inhibitor.. A TNFa inhibitor includes any agent (or.
substance) that interferes with TNFa activity. In a preferred embodiment, the
TNFa
inhibitor can neutralize TNFa activity, particularly detrimental TNFa.
activity which is
associated with disorders in which TNFa activity is detrimental, including,
but not
limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing
spondylitis,
Crohn's disease, psoriasis, and psoriatic arthritis.
In one embodiment, the TNFa inhibitor used in the invention is an anti-TNFa
antibody (also referred to herein as a TNFa antibody), or an antigen-binding
fragment
thereof, including chimeric, humanized, and human antibodies. Examples of TNFa
antibodies that may be used in the invention include, but not limited to,
infliximab
(Remicade, Johnson and Johnson; described in U.S. Patent No. 5,656,272),
CDP57I (a humanized monoclonal anti-TNF-alpha IgG4
antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibody fragment),
an
anti-TNF dAb (Peptech), CNTO=148 (golimumabNedarex and Centocor, see WO
02/1202), and acialiniu.rnab (IIUMIRAe Abbott Laboratories: a human anti--TNF
mAb,
= . .
described in US 6,090,382 as D2E7). Additional TNF antibodies that may be used
in
the invention are described in U.S. Patent Nos. 6,593,458;.6,498,237;
6,451,983; and
6,448,380.
Other examples of TNFa inhibitors which may be used in the methods and
compositions of the invention include etanercept (Enbrel, described in WO
91/03553
and WO 09/406476), soluble TNF receptor Type I; a pegylated soluble TNF
receptor
Type I (PEGs TNF-R1), p55TNFR1gG (Lenercept), and recombinant TNF binding
protein (r-TBP-I) (Serono). Examples of TNFa inhibitors include but are not
limited to
infliximab (RemicadeTm), CDP 571, CDP 870, anti-TNF dAb, golimumab,
adalimumab,
etatiercept (EnbrelTm), p.55TNFR I gG (Lenercept) and r-TBP-1. A particularly
preferred
TNFa inhibitor is adalimumab (HUMIRe).
CA 02950817 2016-12-07
47
In one embodiment, the term "TNFa inhibitor" excludes infliximab. In one
embodiment, the term "TNFa inhibitor" excludes adalimumab. In another
embodiment,
the term "TNFa inhibitor" excludes adalimumab and infliximab.
In one embodiment, the term "TNFa inhibitor" excludes etanercept, and,
optionally, adalimumab, infliximab, and adalimumab and infliximab.
In one embodiment, the term "TNFa antibody" excludes infliximab. In one
embodiment, the term "TNFa antibody" excludes adalimumab. In another
embodiment,
the term "TNFa antibody" excludes adalimumab and infliximab.
In one embodiment, the invention features uses and composition for treating or
determining the efficacy of a TNFa inhibitor for the treatment of rheumatoid
arthritis,
wherein the TNFa antibody is an isolated human antibody, or antigen-binding
portion
thereof, that binds to human TNFa with high affinity and a low off rate, and
also has a
high neutralizing capacity. Preferably, the human antibodies used in the
invention are
recombinant, neutralizing human anti-hTNFa antibodies. The most preferred
recombinant, neutralizing antibody of the invention is referred to herein as
D2E7, also
referred to as HUMIRA or adalimumab (the amino acid sequence of the D2E7 VL
region is shown in SEQ ID NO: 1; the amino acid sequence of the D2E7 VH region
is
shown in SEQ ID NO: 2). The properties of D2E7 (adalimumab / HUMIRA ) have
been described in Salfeld etal., U.S. Patent Nos. 6,090,382, 6,258,562, and
6,509,015.
The methods of the invention may also
be performed using chiMeric and humanized murine anti-hTNFa antibodies which
have
undergone clinical testing for treatment of rheumatoid arthritis (see e.g.,
Elliott, M.J., et
al. (1994) Lancet 344:1125-1127; Elliot, M.J., et at. (1994) Lancet 344:1105-
1110;
Rankin, E.C., et al. (1995) Br. J. RheumataL 34:334-342).
In one embodiment, the method of the invention includes determining the
efficacy of adalimumab antibbdies and antibody portions, adalimumab-related
antibodies and antibody portions, or other human antibodies and antibody
portions with
equivalent properties to adalimumab, such as high affinity binding to hTNFa
with low
dissociation kinetics and high neutralizing capacity, for the treatment of
rheumatoid
arthritis. In one embodiment, the invention provides treatment with an
isolated human
antibody, or an antigen-binding portion thereof, that dissociates from human
TNFa with
a Kj of 1 x 10-8 M or less and a Koff rate constant of! x 10-3 s-1 or less,
both
CA 02950817 2016-12-07
48
determined by surface plasmon resonance, and neutralizes human TNFa
cytotoxicity in
a standard in vitro L929 assay with an IC50 of 1 x 10-7 M or less. More
preferably, the
isolated human antibody, or antigen-binding portion thereof, dissociates from
human
TNFa with a Koff of 5 x 10-4 s-1 or less, or even more preferably, with a Koff
of 1 x
10-'4 s--1 Or less: More preferably, the isolated human antibody, or
antigen:binding
portion thereof, neutralizes human TNFa cytotoxicity in a standard in vitro
L929 assay
with an IC50 of 1 x 10-8 M or less, even more preferably with an IC50 of 1 x
10-9 M or
less and still more preferably with an IC50 of 1 x 10-10 M or less. In a
preferred
embodiment, the antibody is an isolated human recombinant antibody, or an
antigen-
binding portion thereof.
It is well known in the art that antibody heavy and light chain CDR3 domains
play an important role in the binding specificity/affinity of an antibody for
an antigen.
Accordingly, in another aspect, the invention pertains to treating Crohn's
disease by
administering human antibodies that have slow dissociation kinetics for
association with
hTNFa and that have light and heavy chain CDR3 domains that structurally are
identical
= to or related to those of D2E7. Position 9 of the D2E7 VL CDR3 can be
occupied by
Ala or Thr without substantially affecting the Koff. Accordingly, a consensus
motif for
the D2E7 VL CDR3 comprises the amino acid sequence: Q-R-Y-N-R-A-P-Y-(T/A)
(SEQ ID NO: 3). Additionally, position 12 of the D2E7 CDR3 can be
occupied by
Tyr or Asn, without substantially affecting the Koff. Accordingly, a consensus
motif for
the D2E7 VH CDR3 comprises the amino acid sequence: V-S-Y-L-S-T-A-S-S-L-D-
(Y/N) (SEQ ID NO: 4). Moreover, as demonstrated in Example 2 of U.S. Patent
No.
6,090,382, the CDR3 domain of the D2E7 heavy and light chains is amenable to
substitution with a single alanine residue (at position 1, 4, 5, 7 or 8 within
the VL CDR3
or at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 within.the VH CDR3) without
substantially
affecting the Koff. Still further, the skilled artisan will appreciate that,
given the
amenability of the D2E7 VL and VII CDR3 domains to substitutions by alanine,
substitution of other amino acids within the CDR3 domains may be possible
while still
retaining the low off rate constant of the antibody, in particular
substitutions with
conservative amino acids. Preferably, no more than one to five conservative
amino acid
substitutions are made within the D2E7 VL and/or VH CDR3 domains. More
CA 02950817 2016-12-07
49
preferably, no more than one to three conservative amino acid substitutions
are made
within the D2E7 VL and/or VH CDR3 domains. Additionally, conservative amino
acid
substitutions should not be made at amino acid positions critical for binding
to hTNFa.
Positions 2 and 5 of the D2E7 VL CDR3 and positions 1 and 7 of the D2E7 VH
CDR3
appear to be critical for interaction with hTNFoc and thus, conservative amino
acid
substitutions preferably are not made at these positions (although an alanine
substitution
at position 5 of thc D2E7 VL CDR3 is acceptable, as described above) (see U.S.
Patent
No. 6,090,382).
Accordingly, in another embodiment, the antibody or antigen-binding portion
thereof preferably contains the following characteristics:
a) dissociates from human TNFa with a Koff rate constant of] x 10-3 s-1 or
less, as determined by surface plasmon resonance;
b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ
ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at
position I,
4, 5, 7 Or 8 or by one to five conservative amino acid substitutions at
positions 1, 3, 4, 6,
7, Sand/or 9;
= c) has.a heavy chain CDR3 domain comprising the amino atid sequence of
SEQ
ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at
position 2,
3,4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid
substitutions at
positions 2, 3,4, 5, 6, 8,9, 10, 11 and/or 12.
More preferably, the antibody, or antigen-binding portion thereof, dissociates
. . ,
from human TNFa with a Koff of 5 x10-4 s-' or less. Even more preferably, the
= = . . . .
antibody, or antigen-binding portion thereof, dissociates from human TNFa with
a Koff
of Ix 10-4 s-1 or less.
In yet another embodiment, the antibody or antigen-binding portion thereof
preferably contains a light chain variable region (LCVR) having a CDR3 domain
comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID
NO: 3
by a single alanine substitution at position 1, 4, 5, 7 or 8, and with a heavy
chain variable
region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ
ID
NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at
position 2, 3,
4, 5, 6, 8, 9, 10 or 11. Preferably, the LCVR further has a CDR2 domain
comprising the
amino acid sequence of SEQ ID NO: 5 (i.e., the D2E7 VL CDR2) and the HCVR
further
CA 02950817 2016-12-07
has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6 the
D2E7 VII CDR2). Even more preferably, the LCVR further has CDRI domain
comprising the amino Acid sequence of SEQ ID NO: 7 (i.e., the D2E7 VL CDRI)
and
. the HCVR has a CDRI domain comprising the amino acid sequence of SEQ ID NO:
8
5 (i.e., the 02E7 VH CDRI). The framework regions for VL preferably are
from the VKI
human germ line family, more preferably from the A20 human germ line Vk gene
and
most preferably from the D2E7 VL framework sequences shown in Figures IA and
IB
of U.S. Patent No. 6,090,382. The framework regions for VH preferably are from
the
VH3 human germ line family, more preferably from the DP-31 human germ line VH
10 gene and most preferably from the D2E7 VH framework sequences shown in
Figures 2A
and 2B of U.S. Patent No. 6,090,382.
Accordingly, in another embodiment, the antibody or antigen-binding portion
thereof preferably contains a light chain variable region (LCVR) comprising
the amino
acid sequence of SEQ ID NO: 1 (i.e., the D2E7 VL) and a heavy chain variable
region
. .
15 (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 (i.e., the
D2E7 VH). In
certain embodiments, the antibody comprises a heavy chain constant region,
such as an
IgGl, IgG2, IgG3, .1gG4, IgA, IgE, IgM or IgD constant region. Preferably, the
heavy
chain constant region is an IgG1 heavy chain constant region or an IgG4 heavy
chain
constant region. Furthermore, the antibody can comprise a light chain constant
region,
20 either a kappa light chain constant region or a lambda light chain
constant region.
Preferably, the antibody comprises a kappa light chain constant region.
Alternatively,
the antibody portion can be, for example, a Fab fragment or a single chain Fv
fragment.
In still other embodiments, the invention includes uses of an isolated human
antibody, or antigen-binding portion thereof, containing 02E7-related VL and
VH
25 CDR3 domains. For example, antibodies, or antigen-binding portions
thereof, with a
light chain variable region (LCVR) having a CDR3 domain comprising an amino
acid
sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 11,
SEQ ID
NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO.: 15, SEQ 1D NO: 16, SEQ ID
NO:. 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID
30 NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26 or
with
a heavy chain variable region (HCVR) having a CDR3 domain comprising an amino
acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO:
27,
CA 02950817 2016-12-07
51
SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32,
SEQ ID NO: 33, SEQ ID NO: 34 and SEQ ID NO: 35.
The TNFa antibody used in the methods and compositions of the invention may
be modified for improved treatment of rheumatoid arthritis. In some
embodiments, the
TNFct antibody or antigen binding fragments thereof, is chemically modified to
provide
a desired effect. For example, pegylation of antibodies and antibody fragments
of the
invention may be carried out by any of the pegylation reactions known in the
art, as
described, for example, in the following references: Focus on Growth Factors
3:4-10
(1992); EP 0 154 316; and EP 0 401 384.
Preferably, the pegylation is can-led out via an acylation reaction
or an alkylation reaction with a reactive polyethylene glycol molecule (or an
analogous
reactive water-soluble polymer). A preferred water-soluble polymer for
pegylation of
the antibodies and antibody fragments of the invention is polyethylene glycol
(PEG). As
used herein, "polyethylene glycol" is meant to encompass any of the forms of
PEG that
have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or
aryloxy-
polyethylene glycol.
= Methods for preparing pegylated antibodies and antibody fragments of the
invention will generally comprise the steps of (a) reacting the antibody or
antibody
fragment with polyethylene glycol, such as a reactive ester or aldehyde
derivative of
PEG, under conditions whereby the antibody or antibody fragment becomes
attached to
one or more PEG groups, and (b) obtaining the reaction products. It will be
apparent to
one of ordinary skill in the art to select the optimal reaction conditions or
the acylation
reactions based on known parameters and the desired result.
= Pegylated antibodies and antibody fragments may generally be used to
treat
rheumatoid arthritis by administration of the TNFa antibodies and antibody
fragments
described herein. Generally the pegylated antibodies and antibody fragments
have
increased half-life, as compared to the nonpegylated antibodies and antibody
fragments.
The pegylated antibodies and antibody fragments may be employed alone,
together, or
in combination with other pharmaceutical compositions.
In yet another embodiment of the invention, TNFa, antibodies or fragments
thereof can be altered wherein the constant region of the antibody is modified
to reduce
at least one constant region-mediated biological effector function relative to
an
unmodified antibody. To modify an antibody of the invention such that it
exhibits
CA 02950817 2016-12-07
52
reduced binding to the Fc receptor, the immunoglobulin constant region segment
of the
antibody can be mutated at particular regions necessary for Fc receptor (FcR)
interactions (see e.g., Canfield, S.M. and S.L. Morrison (1991)]. Exp. Med.
173:1483-
1491; and Lund, J. el al.- (1991) J. of Immunol. 147:2657-2662). Reduction in
FcR
binding ability of the antibody may also reduce other effector functions that
rely on FcR
interaCtions, such as opsonization and phagocytosis and antigen-dependent
cellular
cytotoxicity.
An antibody or antibody portion used in the compositions and methods of the
invention can be derivatized or linked to another functional molecule (e.g.,
another
peptide of protein). Accordingly, the antibodies and antibody portions of the
invention
are intended to include derivatized and otherwise modified forms of the human
anti-
hTNFa antibodies described herein, including immunoadhesion molecules. For
example, an antibody or antibody portion of the invention can be functionally
linked (by
chemical coupling, genetic fusion, noncovalent association or otherwise) to
one or more
other molecular entities, such as another antibody (e.g., a bispecific
antibody or a
diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent,
and/or a protein
or peptide that can mediate associate of the antibody or antibody portion with
another
molecule (such as a streptavidin core region or a polyhistidine tag).
One type of derivatized antibody is produced by crosslinking two or more
antibodies (of the same type or of different types, e.g., to create bispecific
antibodies).
Suitable crosslinkers include those that are heterobifunctional, having two
distinctly
reactive groups separated by an appropriate spacer (e.g., m-maleimidobenzoyl-N-
hydroxysuccinimide ester) or homobifunctional (e.g., disucciaimidyl suberate).
Such
linkers are available from Pierce Chemical Company, Rockford, IL. '
Useful detectable agents with which an antibody or antibody portion of the
invention may be derivatized include fluorescent compounds. Exemplary
fluorescent
detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine,
5-
dimethylamine-1 -napthalenesulfonyl chloride, phycoerythrin and the like. An
antibody
may also be derivatized with detectable enzymes, such as alkaline phosphatase,
horseradish peroxidase, glucose oxidase and the like. When an antibody is
derivatized
with a detectable enzyme, it is detected by adding additional reagents that
the enzyme
uses to produce a detectable reaction product. For example, when the
detectable agent
horseradish peroxidase is present, the addition of hydrogen peroxide and
CA 02950817 2016-12-07
53
diaminobenzidine leads to a colored reaction product, which is detectable. An
antibody
may also be derivatized with biotin, and detected through indirect measurement
of
avidin or streptavidin binding.
An antibody, or antibody portion, used in the methods and compositions of the
invention, can be prepared by recombinant expression of inununoglobulin light
and
heavy chain genes in a host cell. To express an antibody recombinantly, a host
cell is
transfected with one or more recombinant expression vectors carrying DNA
fragments
encoding the irrununoglobulin light and heavy chains of the antibody such that
the light
and heavy chains are expressed in the host cell and, preferably, secreted into
the medium
in which the host cells are cultured, from which medium the antibodies can be
recovered. Standard recombinant DNA methodologies are used to obtain antibody
heavy and light chain genes, incorporate these genes into recombinant
expression
vectors and introduce the vectors into host cells, such as those described in
Sambrook,
Fritsch and Maniatis (eds), Molecular Cloning; A Laboratory Manual, Second
Edition,
Cold Spring Harbor, N.Y., (1989), Ausu. bel,'F.M. et aL (eds.) Current
ProtocOls in
Molecular Biology, Greene Publishing Associates, (1989) and in U.S. Patent No.
4,816,397 by Boss et al.
To express adalimumab (D2E7) or an adalimumab (D2E7)-related antibody,
DNA fragments encoding the light and heavy chain variable regions are first
obtained.
These DNAs can be obtained by amplification and modification of germline light
and
heavy chain variable sequences using the polymerase chain reaction (PCR).
Germline
DNA sequences for human heavy and light chain variable region genes are known
in the
art (see e.g., the "Vbase" human germline sequence database; see also Kabat,
B.A., et al.
(1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S.
Department
of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, LM.,
etal.
(1992) "The Repertoire of Human Germline VH Sequences Reveals about Fifty
Groups
of VH Segments with Different Hypervariable Loops" J. Mot Biol. 227:776-798;
and
Cok, J.P.L. etal. (1994) "A Directory of Human berm-line V7g Segments Reveals
a
Strong Bias in their Usage" Eur. .1 Immunol. :827-836).24
To obtain a DNA fragment encoding
the heavy chain variable region of D2E7, or a D2E7-related antibody, a member
of the
VH3 family of human gerrnline VH genes is amplified by standard PCR. Most
preferably, the DP-31 VH gerrnline sequence is amplified. To obtain a DNA
fragment
CA 02950817 2016-12-07
54
encoding the light chain variable region of D2E7, or a D2E7-related antibody,
a member
of the VKI family of human germline VL genes is amplified by standard PCR.
Most
preferably, the A20 VL germline sequence is amplified. PCR primers suitable
for use in
amplifying the DP-31 germline VH and A20 germline VL sequences can be designed
based on the nucleotide sequences disclosed in the references cited supra,
using standard
methods.
Once the germline VH and VL fragments are obtained, these sequences can be
mutated to encode the D2E7 or D2E7-related amino acid sequences disclosed
herein.
The, amino acid sequences encoded by the germline VH and VL DNA sequences are
first compared to the D2E7 or D2E7-related VH and VL amino acid sequences to
identify amino acid residues in the D2E7 or D2E7-related sequence that differ
from
germline. Then, the appropriate nucleotides of the germline DNA sequences are
mutated such that the mutated germline sequence encodes the D2E7 or D2E7-
related
amino acid sequence, using the genetic code to determine which nucleotide
changes
should be made. Mutagenesis of the gerrnline sequences is carried out by
standard
methods, such as PCR-mediated mutagenesis (in which the mutated nucleotides
are
incorporated into the PCR primers such that the PCR product contains the
mutations) or
site-directed mutagenesis.
-= = Moreover, it should be noted that if the rgermline" sequences obtained by
PCR
amplification encode amino acid differences in the framework regiOns from the
true
germline configuration (i.e., differences in the amplified sequence as
compared to the
true germline sequence, for example as a result of somatic mutation), it may
be desirable
to change these amino acid differences back to the true germline sequences
(i.e.,
"backmutation" of framework residues to the germline configuration).
Once DNA fragments encoding D2E7 or D2E7-related VH and VL segments are
obtained (by amplification and mutagenesis of germline VH and VL genes, as
described
above), these DNA fragments can be further manipulated by standard recombinant
DNA
techniques, for example to convert the variable region genes to full-length
antibody
chain genes, to Fab fragment genes or to a seFv gene. In these manipulations,
a VL- or
VH-encoding DNA fragment is operatively linked to another DNA fragment
encoding
another protein, such as an antibody constant region or a flexible linker. The
term
"operatively linked", as used in this context, is intended to mean that the
two DNA
CA 02950817 2016-12-07
fragments are joined such that the amino acid sequences encoded by the two DNA
fragments remain in-frame.
The isolated DNA encoding the VH region can be converted to a full-length
heavy chain gene by operatively linking the VH-encoding DNA to another DNA
5 molecule encoding heavy chain constant regions (CHI, CH2 and CH3). The
sequences
of human heavy chain constant region genes are known in the art (see e.g.,
Kabat, E.A.,
et al. (1991)Sequences of Proteins of Immunological Interest, Fifth Edition,
U.S.
Department of Health and Human Services, NIH Publication No. 91-3242) and DNA
fragments encompassing these regions can be obtained by standard PCR
amplification.
10 The heavy chain constant region can be an IgGI, IgG2, IgG3, IgG4, IgA,
IgE, IgM or
IgD constant region, but most preferably is an IgG1 or IgG4 constant region.
For a Fab
fragment heavy chain gene, the VH-encoding DNA can be operatively linked to
another
DNA molecule encoding only the heavy chain CHI constant region.
= The isolated DNA encoding the VL region can be converted to a full-length
light
15 chain gene (as well as a Fab light chain gene) by operatively linking
the VL-encoding
DNA to another DNA molecule encoding the light chain constant region, CL. The
sequences of human light chain constant region genes are known in the art (see
e.g.,
Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest,
Fifth
Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-
3242)
20 and DNA fragments encompassing these regions can be obtained by standard
PCR
amplification. The light chain constant region can be a kappa or lambda
constant region,
but most preferably is a kappa constant region.
To create a say gene, the VH- and VL-encoding DNA fragments are operatively
linked-to another fragment encoding a flexible linker, .e.g., encoding the
amino acid
25 sequence (Gly4-Ser)3, such that the VH and VL sequences can be expressed
as a
contiguous single-chain protein, with the VL and VH regions joined by the
flexible
linker (see e.g., Bird etal. (1988) Science 242:423-426; Huston etal. (1988)
Proc. Natl.
Ace; d. Sci. USA 85:5879-5883; McCafferty et al., Nature (1990) 348:552-554).
To express the antibodies, or antibody portions used in the invention, DNAs
30 encoding partial or full-length light and heavy chains, obtained as
described above, are
inserted into expression vectors such that the genes are operatively linked to
transcriptional and translational control sequences. In this context, the term
"operatively
linked" is intended to mean that an antibody gene is ligated into a vector
such that
CA 02950817 2016-12-07
56
transcriptional and translational control sequences within the vector serve
their intended
function of regulating the transcription and translation of the antibody gene.
The
expression vector and expression control sequences are chosen to be compatible
with the
expression host cell used. The antibody light chain gene and the antibody
heavy chain
gene can be inserted into separate vector or, more typically, both genes are
inserted into
the same expression vector. The antibody genes are inserted into the
expression vector
by standard methods (e.g., ligation of complementary restriction Ales on the
antibody
gene fragment and vector, or blunt end ligation if no restriction sites are
present). Prior
to insertion of the D2E7 or D2E7-related light or heavy chain sequences, the
expression
vector may already carry antibody constant region *sequences. For example, one
approach to converting the D2E7 or D2E7-related VH and VL sequences to full-
length
antibody genes is to insert them into expression vectors already encoding
heavy chain
constant and light chain constant regions, respectively, such that the VH
segment is=
operatively linked to the CH segment(s) within the vector and the VL segment
is
operatively linked to the CL segment within the vector. Additionally or
alternatively,
the:tecombinant expression vector can encode a signal peptide that facilitates
secretion
of the antibody chain from a host cell. The antibody chain gene can be cloned
into the
vector such that the signal peptide is linked in-frame to the amino terminus
of the
antibody chain gene. The signal peptide can be an immunoglobulin signal
peptide or a
heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin
protein).
= In addition to the antibody chain genes, the recombinant expression
vectors of
the invention carry regulatory sequences that control the expression of the
antibody
chain genes in a host cell. The term "regulatory sequence" is intended to
include
promoters, enhancers and other expression control elements (e.g.,
polyadenylation
signals) that control the transcription or translation of the antibody chain
genes. Such
regulatory sequences are described, for example, in Goeddel; Gene Expression
Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990).
It
will be appreciated by those skilled in the art that the design of the
expression vector,
including the selection of regulatory sequences may depend on such factors as
the choice
of the host.cell to be transformed, the level of expression of protein
desired, etc.
Preferred regulatory sequences for mammalian host cell expression include
viral
elements that direct high levels of protein expression in mammalian cells,
such as
promoters and/or enhancers derived from cromegalovirus (CMV) (such as the CMV
CA 02950817 2016-12-07
57
promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40
promoter/enhancer),
adenovirus, (e.g., the adenovirus major late promoter (AdMLP)) and polyoma.
For
further description of viral regulatory elements, and sequences thereof, scc
e.g., U.S.
Patent No. 5,168,062 by Stinski, U.S. Patent No. 4,510,245 by Bell e/ al. and
U.S. Patent
No. 4,968,615 by Schaffner eral.
.. In additipn to the antibody chain genes and regulatory sequences, the
..
recombinant expression vectors used in the invention may carry additional
sequences,
such as sequences that regulate replication of the vector in- host cells
(e.g., origins of
replication) and selectable marker genes. The selectable marker gene
facilitates
0 selection of host cells into which the vector has been introduced (see
e.g., U.S. Patents
Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.). For example,
typically the
selectable marker gene confers resistance to drugs, such as 0418, hygromycin
or
methotrexate, on a host cell into which the vector has been introduced.
Preferred
selectable marker genes include the dihydrofolate reductase (DHFR) gene (for
use in
'15 dhfr- host cells with methotrexate selection/amplification) and the neo
gene (for 0418
selection).
For expression of the light and heavy chains, the expression vector(s)
encoding
the heavy and light chains is transfected into a host cell by standard
techniques. The
various forms of the term "transfection" are intended to encompass a wide
variety of
20 techniques commonly used for the introduction of exogenous DNA into a
prokaryotic or
eukaryotic host' cell, e.g., electroporation, calcium-phosphate precipitation,
DEAE,
deitran transfection and the like. Although it is theoretically possible to
express the
antibodies of the invention in either prokaryotic or eukaryotic host cells,
expression of
antibodies in eukaryotic cells, and most preferably mammalian host cells, is
the most
25 preferred because such eukaryotic cells, and in particular mammalian
cells, are more
likely than prokaryotic cells to assemble and secrete a properly folded and
immunologically active antibody. Prokaryotic expression of antibody genes has
been
reported to be ineffective for production of high yields of active antibody
(Boss, M.A.
and Wood, C. R. (1985) Immunology Today 6:12-13).
30 Preferred mammalian host cells for expressing the recombinant antibodies
of the
invention include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO
cells,
described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-
4220, used
with a DHFR selectable marker, e.g., as described in R.I. Kaufman and P.A.
Sharp
CA 02950817 2016-12-07
58
(1982) Mol. Biol. 159:601-621), NSO myeloma cells, COS cells and SP2 cells.
When
recombinant expression vectors encoding antibody genes are introduced into
mammalian
host cells, the antibodies are produced by culturing the host cells for a
period of time
sufficient to allow for expression of the antibody in the host cells or, more
preferably,
secretion of the antibody into the culture medium in which the host cells are
grown.
Antibodies can be recovered from the culture medium using standard protein
purification methods.
Host cells can also be used to produce portions of intact antibodies, such as
Fab
fragments or scFv molecules. It is understood that variations on the above
procedure are
within the scope of the present invention. For example, it may be desirable to
transfect a
host cell with DNA encoding either the light chain or the heavy chain (but not
both) of
an antibody of this invention. Recombinant DNA technology may also be used to
=
remove some or all of the DNA encoding either or both of the light and heavy
chains
that is not necessary for binding to hTNFa. The molecules expressed from such
truncated DNA molecules are also encompassed by the antibodies of the
invention. In
addition, bifunctional antibodies may be produced in which one heavy and one
light
chain are an antibody of the invention and the other heavy and light chain are
specific
for an antigen other than hTNFa by crosslinking an antibody of the invention
to a
second antibody by standard chemical crosslinking methods.
In a preferred system for recombinant expression of an antibody, or antigen-
binding portion thereof, of the invention, a recombinant expression vector
encoding both
the antibody heavy chain and the antibody light chain is introduced into dhfr-
CHO cells
by calcium phosphate-mediated transfection. Within the recombinant expression
vector,
the antibody heavy and light chain genes are each operatively linked to CMV
enhan- cer/AdMLP promoter regulatory elements to drive high levels of
transcription of
the genes. The recombinant expression vector also carries a DHFR gene, which
allows
for selection of CHO cells that have been transfected with the vector using
methotrexate
selection/amplification. The selected transformant host cells are culture to
allow for
expression of the antibody heavy and light chains and intact antibody is
recovered from
the culture medium. Standard molecular biology techniques are used to prepare
the
recombinant expression vector, transfect the host cells, select for
transformants, culture
the host cells and recover the antibody from the culture medium.
CA 02950817 2016-12-07
59
In view of the foregoing, nucleic acid, vector and host cell compositions that
can
be used for recombinant expression of the antibodies and antibody portions
used in the
invention include nucleic acids, and vectors comprising said nucleic acids,
comprising
the human TNFa antibody adalimumab (D2E7). The nucleotide sequence encoding
the
D2E7 light chain variable region is shown in SEQ ID NO: 36. The CDR1 domain of
the
LCVR encompasses nucleotides 70-102, the CDR2 domain encompasses nucleotides
148-168 and the CDR3 domain encompasses nucleotides 265-291. The nucleotide
sequence encoding the D2E7 heavy chain variable region is shown in SEQ ID NO:
37.
The CDR1 domain of the HCVR encompasses nucleotides 91-105, the CDR2 domain
encompasses nucleotides 148-198 and the CDR3 domain encompasses nucleotides
295-
330. It will be appreciated by the skilled artisan that nucleotide sequences
encoding
D2E7-related antibodies, or portions thereof (e.g., a CDR domain, such as a
CDR3
domain), can be derived from the nucleotide sequences encoding the D2E7 LCVR
and
HCVR using the genetic code and standard molecular biology techniques.
= Recombinant human antibodies of the invention in addition. to D2E7 or an
antigen binding-portion thereof, or D2E7-related antibodies-disclosed herein
can be- .
isolated by screening of a recombinant combinatorial antibody library,
preferably a scFv
phage display library, prepared using human VL and VH cDNAs prepared from mRNA
derived from human lymphocytes. Methodologies for preparing and screening such
libraries are known in the art. In addition to commercially available kits for
generating
phage display libraries (e.g., the Pharmacia Recombinant Phage Antibody
System,
catalog no. 27-9400-01; and the Stratagene SurIZAPTM phage display kit,
catalog no.
240612), examples of methods and reagents particularly amenable for use in
generating
and screening antibody display libraries can be found in, for example, Ladner
et al. U.S.
Patent No. 5,223,409; Kang et al. PCT Publication No. WO 92/18619; Dower etal.
PCT
Publication No. WO 91/17271; Winter etal. PCT Publication No. WO 92/20791;
Markland et al. PCT Publication No. WO 92/15679; Breitling etal. PCT
Publication No.
WO 93/01288; McCafferty etal. PCT Publication No. WO 92/01047; Garrard et aL
PCT PublicationNo. WO 92/09690; Fuchs etal. (1991) Bio/TechnologP 9:1370-1372;
Hay it al. (1992) Hum Antibod Hybridomas 3:81165; Huse et aL (1989) Science
2461275-1281; McCafferty et aL, Nature (1990) 348:552-554; Griffiths et aL
(1993)
EMBO J12:725-734; Hawkins et al. (1992)J Mol Bid l 226:889-896; Clackson et
al.
(1991) Nature 352:624-628; Gram etal. (1992) PNAS 89:3576-3580; Garrard etal.
CA 02950817 2016-12-07
(1991) Bio/Technology 2.: 1373-1377; Hoogenboom etal. (1991) Nuc Acid Res
19:4133-
4137; and Barbas etal. (1991) PNAS 88:7978-7982.
In a preferred embodiment, to isolate human antibodies with high affinity and
a
low off rate constant for hTNFa, a murine anti-hTNFa antibody having high
affinity
5 and a low off rate constant for hTNFa (e.g., MAK 195, the hybridoma for
which has
deposit number ECACC 87 050801) is first used to select human heavy and light
chain
sequences having similar binding activity toward hTNFa, using the epitope
imprinting
methods described in Ho¨ogenboom et al., PCT Publication No:VO 93/06213. The
antibcidy libraries used in this method are preferably scPv libraries prepared
and
10 screened as described in McCafferty etal., PCT Publication No. WO
92/01047,
McCafferty etal., Nature (1990) 348:552-554; and Griffiths etal., (1993) EMBO
J
12:725-734. The scFv antibody libraries preferably are screened using
recombinant
human TNFcr as the antigen.
Once initial human VL and VII segments are selected, "mix and match"
15 experiments, in which different pairs of the initially selected VL and
VH segments are
screened for hTNFa binding, are performed to select preferred VL/VH pair
combinations. Additionally, to flu-ther improve the affinity and/or lower the
off rate
constant for hTNFa binding, the VL and VII segments of the preferred VUVH
pair(s)
can be randomly mutated, preferably within the CDR3 region of VH and/or VL, in
a
20 process analogous to the in vivo somatic mutation process responsible
for affinity
maturation of antibodies during a natural immune response. This in vitro
affinity
maturation can be accomplished by amplifying VH and VL regions using PCR
primers
complimentary to the VITCDR3 or VL CDR3, respectively, which primers have been
"spiked" with a random mixture of the four nucleotide bases at certain
positions such
25 that the resultant PCR products encode VII and VL segments into which
random
mutations have been introduced into the VH and/or VL CDR3 regions. These
randomly
mutated VH and VL segments can be rescreened for binding to hTNFa and
sequences
that exhibit high affinity and a low off rate for hTNFa binding can be
selected.
Following screening and isolation of an hTNFot antibody of the invention from
a
30 recombinant irrununoglobulin display library, nucleic acid encoding the
selected
antibody can be recovered from the display package (e.g., from the phage
genome) and
subcloned into other expression vectors by standard recombinant DNA
techniques. If
desired, the nucleic acid can be further manipulated to create other antibody
forms of the
CA 02950817 2016-12-07
61
invention (e.g., linked to nucleic acid encoding additional immunoglobulin
domains,
such as additional constant regions). To express a recombinant human antibody
isolated
by screening of a combinatorial library, the DNA encoding the antibody is
cloned into a
recombinant expression vector and introduced into a mammalian host cells, as
described
in further detail in above.
Methods of isolating human neutralizing antibodies with high affinity and a
low
off rate constant for hTNFcc are described in U.S. Patent Nos. 6,090,382,
6,258,562, and
6,509,015,
IV. Substances _for Use in the Automatic Injection Device
The methods and compositions of the invention can be used with automatic
injection devices that administer essentially any substance or medication that
is suitable =
for administration by injection. Typically, the substance or medication will
be in a fluid,
e.g., liquid form, although medications in other forms such as gels or semi-
solids,
slurries, particulate solutions, etc. also may suitable for use if the
automatic injection
device is designed to permit the administration of such forms of the
medication.
' Preferred medications are biological agents, such as antibodies, cytokines,
vaccines, fusion proteins and growth factors. Methods of making antibodies are
described above. -
Non-limiting examples of other biological agents that can be used as the
medication in the automatic injection device include but are not limited to
antibodies to
or antagonists of human cytokines or growth factors, for example, TNF, LT, IL-
1, IL-2,
IL-3, 1L-4, IL-5, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, IL-21, IL-23,
interferons, EMAP-
II, GM-CSF, FGF, and PDGF; antibodies to cell surface molecules such as CD2,
CD3,
CD4, CD8, CD25, CD28; CD30, CD40, CD45; CD69, C080 (B7.1), CD86 (B7.2), =
CD90,CTLA or their ligands including C1i154 (gp39 or CD4OL); TNFa converting
enzyme.(TACE) inhibitors; IL-1 inhibitors (Interleulcin-l-converting enzyme
inhibitors,
IL-IRA etc.); Interleukin 11; IL-18 antagonists including IL-18 antibodies or
soluble IL-
18 receptors, or IL-18 binding proteins; non-depleting anti-CD4 inhibitors;
antagonists
of the co-stimulatory pathway CD80 (137.1) or CD86 (B7.2) including
antibodies,
soluble receptors or antagonistic ligands; agents which interfere with
signalling by
proinflammatory cytokines such as TNFct or IL-1 (e.g. IRAK, NIK, HU( , p38 or
MAP
kinase inhibitors); IL-113 converting enzyme (ICE) inhibitors; T-cell
signalling inhibitors
CA 02950817 2016-12-07
62
such as kinase inhibitors; metalloproteinase inhibitors; angiotensin
converting enzyme
inhibitors; soluble cytokine receptors and. derivatives thereof (e.g. soluble
p55 or p75
TNF receptors and the derivatives p75TNFR1gG (EnbrelTm.and p55TNFRIgG
(Lenercept)), sIL-1RI, sIL-IRII, sIL-6R); antiinflammatory cytokines (e.g. 1L-
4, IL-10,
IL-11, IL-13 and TGF-beta); Rituximab; IL-1 TRAP; MRA; CTLA4-Ig; IL-18 BP;
anti-
IL-18; anti-IL15; IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4
antibody; IDEC/SmithKline; see e.g., Arthritis & Rheumatism (1995) Vol. 38,
S185);
DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins; Seragen; see e.g.,
Arthritis
& Rheumatism (1993) Vol. 36 1223); Anti-Tao (humanized anti-IL-2Ra; Protein
Design
Labs/Roche); IL-4 (anti-inflammatory cytokine; DNAX/Schering); 1L-10 (SCI-1
52000;
recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering); IL-10 and/or IL-
4
agonists (e.g., agonist antibodies); IL-IRA (IL-1 receptor antagonist;
Synergen/Amgen);
anakinra (Kinerete/Amgen); TNF-bp/s-TNF (soluble TNF binding protein; see
e.g.,
Arthritis & Rheumatism (1996) Vol. 3_9. , No. 9 (supplement), S284; Amer. J.
Physiol. -
Heart and Circulatory Physiology (1995) Vol. 268, pp. 37-42); R973401
- :
(phosphodiesterase Type IV inhibitor; see e.g., :Arthritis & Rheumatism (1996)
Vol. 39.
No. 9 (supplement), S282); MK-966 (COX-2 Inhibitor; see e.g., Arthritis &
Rheumatism
(1996) Vol. 39, No. 9 (supplement), S81); Iloprost (see e.g., Arthritis &
Rheumatism
(1996) Vol. 12, No. 9 (supplement), S82); zap-70 and/or lck inhibitor
(inhibitor of the
tyrosine kinase zap-70 or Ick); VEGF inhibitor and/or VEGF-R inhibitor
(inhibitors of
vascular endothelial cell growth factor or vascular endothelial cell growth
factor
receptor; inhibitors of angiogenesis); TNF-convertase inhibitors; anti-1L-12
antibodies;
anti-1L-18 antibodies; interleukin-1 I (see e.g., Arthritis & Rheumatism
(1996) Vol. 39,
No. 9 (supplement), S296); interleukin-13 (see e.g., Arthritis & Rheumatism
(1996) Vol.
39, No. 9 (supplement), S308); interleukin -17 inhibitors (see e.g., Arthritis
ti
Rheumatism (1996) Vol. 39, No. 9 (supplement), SI20); anti-thymocyte globulin;
anti-
CD4 antibodies; CD5-toxins; ICAM-1 antisense phosphorothioate oligo-
deoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement
receptor 1
(TP10; T Cell Sciences, Inc.); and anti-IL2R antibodies. .
Pharmaceutical compositions may be loaded into the automatic injection device
of the invention for delivery to a user. In one embodiment, antibodies,
antibody-
portions, as well as other TNFa inhibitors, can be incorporated into
pharmaceutical
compositions suitable for administration to a user using the device of the
invention.
CA 02950817 2016-12-07
63
Typically, the pharmaceutical composition comprises an antibody, antibody
portion, or
other TNFa inhibitor, and a pharmaceutically acceptable carrier. As used
herein,
"pharmaceutically acceptable carrier" includes any and all solvents,
dispersion media,
coatings, antibacterial and antifungal agents, isotonic and absorption
delaying agents,
and the like that are physiologically compatible. Examples of pharmaceutically
acceptable carriers include one or more of water, saline, phosphate buffered
saline,
dextrose, glycerol, ethanol and the like, as well as combinations thereof. In
many cases,
it is preferable to.include isotonic agents, for example, sugars, polyalcohols
such as
. .
mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically
acceptable
carriers may further comprise minor amounts of auxiliary substances such as
wetting or
emulsifying agents, preservatives or buffers, which enhance the shelf life or
effectiveness of the antibody, antibody portion, or other TNFa inhibitor.
The compositions for use in the methods and compositions of the invention may
be in ti variety of forms in accordance with administration via the device of
the
invention, including, for example, liquid solutions (e.g., injectable and
infusible
solutions), dispersions or suspensions. In a preferred embodiment, the
antibody or other
TNFa inhibitor is administered by subcutaneous injection using the device of
the
invention. In one embodiment, the user administers the TNFa inhibitor,
including, but
not limited to, TNFa antibody, or antigen-binding portion thereof, to
himself/herself
using the device of the invention
Therapeutic compositions fypically 'must be-sterile-and stable under the
conditions
of manufacture and storage. The compositioncan be formulated as a solution,
microemulsion, dispersion, liposome, or other ordered structure suitable to
high drug
concentration. Sterile injectable solutions can be prepared by incorporating
the active
compound (i.e., antibody, antibody portion, or other TNFa inhibitor) in the
required
amount in an appropriate solvent with one or a combination of ingredients
enumerated
above, as required, followed by filtered sterilization. Generally, dispersions
are prepared
by incorporating the active compound into a sterile vehicle that contains a
basic dispersion
medium and the required other ingredients from those enumerated above. In the
case of
sterile powders for the preparation of sterile injectable solutions, the
preferred methods of
preparation are vacuum drying and freeze-drying that yields a powder of the
active
ingredient plus any additional desired ingredient from a previously sterile-
filtered solution
thereof. The proper fluidity of a solution can be maintained, for example, by
the use of a
CA 02950817 2016-12-07
64
coating such as lecithin, by the maintenance of the required particle size in
the case of
dispersion and by the use of surfactants. Prolonged absorption of injectable
compositions
can be brought about by including in the composition an agent that delays
absorption, for
example, monostearate salts and gelatin.
In one embodiment, the invention includes an automatic injection device, e.g,,
autoinjector pen, comprising an effective TNFat inhibitor and a
pharmaceutically
acceptable carrier. Thus, the invention provides a prefilled automatic
injection device
comprising a TNFa inhibitor.
In one embodiment, the antibody or antibody portion for use in the methods of
the
invention is incorporated into a pharmaceutical formulation as described in
PCT/11303/04502 and U.S. Appin. No. 20040033228.
This formulation includes a concentration 50 mg/ml of the antibody D2E7
(adalimumab),
wherein one autoinjector pen comprises 40 mg of antibody for subcutaneous
injection. In
one embodiment, the automatic injection device of the invention (or more
specifically the
syringe of the device) comprises a formulation of adalimumab having the
following
formula: adalimumab, sodium chloride, monobasic sodium phosphate dihydrate,
dibasic
sodium phosphate dihydrate, sodium citrate, citric acid monohydrate, mannitol,
polysorbate 80 and water, e.g., water for injection. In another embodiment,
the automatic
injection device comprises a volume of adalimumab including 40 rag adalimumab,
4.93
mg sodium chloride, 0.69 mg monobasic sodium phosphate dihydrate, 1.22 mg
dibasic
sodium phosphate dihydrate, 0.24 mg sodium citrate, 1.04 mg citric acid
monohydrate, 9.6
mg mannitol, 0.8 mg polysorbate 80 and water, e.g., water for injection. In
one
embodiment, sodium hydroxide is added as necessary to adjust pH.
The dose amount of TNFa inhibitor in the automatic injection device may vary
according to the disorder' for which the TNFcr inhibitor is being used to
treat. In one
embodiment, the inventionincludes an automatic injection device comprising a
dose of
adalimumab of about 20 mg of adalimumab; 40 mg of adalimumab; 80 mg of
adalimumab; and 160 mg of adalimumab. It should be noted that for all ranges
described
herein, including the dose ranges, all numbers intermediary to the recited
values are
included in the invention, e.g., 36 mg of adalimumab, 48 mg of adalimumab,
'etc. In
addition ranges recited using said numbers are also included, e.g., 40 to 80
mg of
adalimumab. The numbers recited herein are not intended to limit the scope of
the
invention.
CA 02950817 2016-12-07
The TNFa antibodies and inhibitors used in the invention may also be
administered in the form of protein crystal formulations that include a
combination of
protein crystals encapsulated within a polymeric carrier to form coated
particles. The
coated particles of the protein-crystal formulation may have a spherical
morphology and
5 be microspheres of up to 500 micro meters in diameter or they may have
some other
morphology and be mieroparticulates. The enhanced concentration of protein
crystals
allows the antibody of the invention to be delivered subcutaneously. In one
embodiment,
the TNFot antibodies of the invention are delivered via a protein delivery
system, wherein
one or more of a protein crystal formulation or composition, is administered
to a user with
10 a INFa-related disorder. Compositions and methods of preparing
stabilized formulations
of whole antibody crystals or antibody fragment crystals are also described in
WO
02/072636, In one
embodiment, a formulation
comprising the crystallized antibody fragments described in PCT/IB03/04502 and
U.S.
Appin. No. 20040033228, is used to
treat rheumatoid
15 arthritis using the methods of the invention.
Supplementary active compounds can also be incorporated into the compositions.
Lh eiriain embodiments, an antibody or antibody portion for use in the medic)*
cis of the
invention is co. formulated with and/or coadministered with one or more
additional
therapeutic agents, including a rheumatoid arthritis inhibitor or antagonist.
For example,
20 an anti-hTNFa antibody or antibody portion may be eoformulated and/or
coadministered
with one or more additional antibodies that bind other targets associated with
TNFct
related disorders (e.g., antibodies that bind other cytokines or that bind
cell surface
molecules), one or more cytokines, soluble TNFa receptor (see e.g., PCT
Publication No.
WO 94/06476) and/or one or more chemical agents that inhibit hINFa production
or
25 activity (such as cyclohexane-ylidene derivatives as described in PCT
Publication No.
WO 93/19751) or any combination thereof. Furthermore, one or more antibodies
of the
invention may be used in combination with two or more of the foregoing
therapeutic
agents. Such combination therapies may advantageously utilize lower dosages of
the
administered therapeutic *agents, thus avoiding possible side effects,
complications or low
..=
30 level of
response by the patient associated with the various monotherapies. Additional
agents that may be used in combination with a INFcc antibody or antibody
portion are
deleribed in US Appin. No. 11/800531
CA 02950817 2016-12-07
66
The automatic injection device, e.g., autoinjector pen, of the invention may
include a "therapeutically effective amount" or a "prophylactically effective
amount" of
an antibody or antibody portion of the invention. A "therapeutically effective
amount"
refers to an amount effective, at dosages and for periods of time necessary,
to achieve
the desired therapeutic result. A therapeutically effective amount of the
antibody,
antibody portion, or other TNFa inhibitor may vary according to factors such
as the
disease state, age, sex, and weight of the individual, and the ability of the
antibody,
.. =
antibody portion, other TNFa inhibitor to elicit a desired response in the
individual. A
therapeutically effective amount is also one in which any toxic or detrimental
effects of
the antibody, antibody portion, or other TNFa inhibitor are outweighed by the
therapeutically beneficial effects. A "prophylactically effective amount"
refers to an
amount effective, at dosages and for periods of time necessary, to achieve the
desired
prophylactic result. Typically, since a prophylactic dose is used in patients
prior to or at
an earlier stage of disease, the prophylactically effective amount will be
less than the
therapeutically effective amount.
=
V. Articles of Manufacture of the Invention
The invention also provides an article of manufacture or kit comprising the
autcimatic injection device of the invention. In one embodiment of the
invention, the kit
comprises an automatic injector device, e.g., an autoinjector pen such as the
HUMIRA
pen, comprising a liquid drug, e.g., a TNFa inhibitor, such as an antibody,
and
instructions for administration of the liquid drug. In one embodiment, the kit
comprises
instructions for delivering a TNFa inhibitor for treatment of a disorder in
which TNFa is
detrimental, e.g., rheumatoid arthritis, using the automatic injection device.
The
instructions may describe how, e.g., subcutaneously, and when, e.g., at week
0, week 2,
week 4, etc., the dose of TNFa inhibitor shall be administered to a patient
for treatment.
An article of manufacture, also referred to herein as a kit, refers to a
packaged
product comprising the automatic injection device of the invention. The kit
preferably -
comprises a box or container that holds the components of the kit, i.e.,
automatic injection
device. In one embodiment, the automatic injection device, e.g., an
autoinjector pen, is
housed in a dose tray within the kit or article. The kit may also include
instructions for
administering a substance, such as a liquid drug, e.g., a TNFa antibody, to a
patient using
the automatic injection device of the invention. The term."package insert" is
used to refer
CA 02950817 2016-12-07
67
to instructions customarily included in commercial packages of therapeutic
products,
including liquid drugs, that contain information about the indications, usage,
dosage,
administration, contraindications and/or warnings concerning the use of such
therapeutic
products. In one embodiment, the package insert is the label for the
therapeutic substance
provided by the kit.
The kit or article of manufacture may include a label or a Food and Drug
Administration approved label, which provides a protocol for using the
automatic
injection device for administering the substance, e.g., TNFa inhibitor. Thus,
the invention
also includes labels used alone or in combination with articles of manufacture
which
provide information to a patient regarding the automatic injection device,
including
information such as how to use the device, what substance, e.g., liquid dose,
the device
holds for administration to a patient, and how to dispose of the device once
administration
is complete. In one embodiment, the label is found on a package insert. In one
embodiment, the label is a package insert that includes a Patient Information
Leaflet
which provides information to a patient regarding how to use the automatic
injection
device of the invention.
The kit or article of manufacture of the invention may contain information
regarding the automatic injection device with respect to how the device is
packaged
within the kit or article. The kit may comprise a dose tray comprising the
automatic
injection device of the invention containing 'a substance, e.g., a TNFa
inhibitor. In one
embodiment, the dose tray is for single use of the device for delivering the
agent. In
another example, the kit may include 2 or more dose trays, each containing an
automatic
injection device, e.g., autoinjector pen._The kit or article of manufacture
may also
indicate related items needed for using the automatic injection device, e.g.,
alcohol
preps, package insert with an attached patient information leaflet, and/or a
patient
information booklet. Such Written material, e.g., package inserts with an
attached
patient information leaflet, and/or a patient information booklet, may be used
to provide
the recipient with information regarding administration techniques, common
adverse
events, disposal information, etc. In one embodiment, the kit or article of
manufacture
of the invention indicates in a manner visible from the outside of the
packaging of the kit
or article, that the kit or article contains 2 dose trays, 2 alcohol preps,
one_package insert
with an attached patient information leaflet, and one patient information
booklet.
CA 02950817 2016-12-07
68
The kit or article of manufacture of the invention may contain information,
for
example on a label, regarding how a liquid dose of a drug, e.g., a TNFcc
inhibitor, such
as a TNFot antibody (adalimumab), is packaged within the automatic injection
device,
e.g,.autoinjector pen, of the invention. For example, in one embodiment, the
label of the
invention may indicate that adalimumab is dispensed in a carton containing 6
alcohol
-preps and 6 dose trays (Crohn's Disease Starter Package). In one embodiment,
the label
also may indicate each dose tray consists of a single-use pen each pen,
containing a 1
mL prefilled glass syringe with a fixed 27 gauge Ya inch needle, providing 40
mg (0.8
mL) of HUMIRA .
In one embodiment the kit or article of manufacture of the invention includes
information indicating that the automatic injection device provided within the
kit
comprises a formulation comprising the human antibody adalimumab (adalimumab /
HUMIRA / D2E7), as described in PCT/1B03/04502 and U.S. Appin. No. 10/222140.
In one embodiment, the kit or article of manufacture of the invention may
contain information, for example on a label, which describes that HUMIRA is
supplied
as a sterile, preservative-free solution of adalimumab for subcutaneous
administration.
The label may further describe that-the drug product is supplied as either
asingle-use, 1
mL prefilled glass syringe or as a single-use, prefilled pen (HUMIRA Pen).
The label
of the invention may indicate that enclosed within the pen is a single-use, 1
mL prefilled
glass syringe. The label of the invention may further indicate that the
solution of
HUMIRA is clear and colorless, with a pH of about 5.2. The label may also
indicate
that HUMIRA (adalimumab) is supplied in pre-filled syringes or in prefilled
pens as a
Fireservative-free, sterile solution for subcutaneous administration. In one
embodiment,
the label indicates that the automatic injection device of the invention
containing
adalimumab is provided in a HUMIRA pen carton, wherein HUMIRA is dispensed
in a carton containing two alcohol preps and two dose trays. The label may
further
specify that each dose tray consists of at least one single-use pen,
containing a 1 mL
prefilled glass syringe with a fixed 27 gauge 1/2 inch needle, providing 40
mg (0.8 mL) of
HUMIRA .
The kit or article of manufacture-ofthe invention may contain information; for
example on a label, which provides information regarding how the automatic
invention
device should appear in the kit and/or how the substance contained within the
automatic
CA 02950817 2016-12-07
69
injection device, e.g., liquid drug, should appear. Such information may be
provided to
insure safety regarding the administration of the substance to a patient, such
that a
patient would know whether the kit and/or automatic injection device had been
tampered
with and/or whether the substance had been compromised such that
administration
should not be performed. In one embodiment, the label indicates that the
solution in the
HUMIRA Pen should be carefully inspected visually for particulate matter and
discoloration prior to subcutaneous administration.
The kit or article of manufacture of the invention may contain information,
for
example on a label, which provides instructions regarding how to use the
automatic =
injection device of the invention, including administration of the substance,
e.g., liquid
drug, held within the device. In one embodiment, the label indicates that
patients using
the HUMIRAS Pen should be instructed to inject the full amount in the syringe
(0.8
mL), which provides 40 mg of HUMIRMO, according to the directions provided in
the
Patient Information Leaflet.
The kit or article of manufacture of the invention may contain information,
for
example on a label, Which provides instruction for preparing to use the pen of
the
invention. For example, the label may provide instructions for setting up for
an injection
with the pen. In one embodiment, the invention provides a pen filled with
HUMIRAO,
wherein a label for said pen may indicate that a patient will need the
following items for
.each dose: one HUMIRAO Pen and 1 alcohol prep (swab). The label may also
indicate
that the patient should find a clean flat working surface. The label may also
indicate that
the-pen-should n'ot be used if seals on top. and bottom of carton are broken
or missing, as
well as, optionally, art indication that the patient should contact their
pharmacist if the
seals are broken. The label may indicate to a patient that he should remove
one dose
tray containing, for example, a pen of HUMIRAOD, from the refrigerator (if the
substance, e.g., liquid drug, requires refrigeration). Additionally, a label
indicating use
of pen filled with HUM1RASID may indicate that a patient should not use a Pen
that is
frozen or if it has been left in direct sunlight. The label may also 'indicate
that if the
patient does not have all of the pieces needed to give an injection, a
pharmacist should
be called. The label may also indicate that the patient should use only the
items
provided in the box the substance, e.g., HIJMIRA4D, comes in.
For labels of the invention relating to an autoinjector pen comprising
adalimumab, the label may indicate that the patient should check and make sure
the
CA 02950817 2016-12-07
name I-IUMIRMi) appears on the dose tray and pen label; that the patient
should check
the expiration date on the dose tray label and the pen label to make sure the
date has not
passed, and, further that the patient should not use a pen if the date has
passed; and that
the patient should have a puncture proof container nearby for disposing of the
used pen.
5 = The kit or article of manufacture may also contain material for use,
either within
the package or through accompanying information, for treatment of the
disorders
described herein. In one embodiment, the packaging Is specific to a disorder
that Is
being treated with a TNF'a antibody, e.g., adalimumab. The kit or article of
manufacture
further can include a second agent (as described herein) packaged with or co-
introduced
10 with instructions for using the second agent with a first agent (as
described herein).
Methods for using the automatic injection device of the invention are
described
in more detail below and in the Examples. Moreover, any of the methods
described
herein relating to the automatic injection device may be included in a label
of the
invention.
VI. Methods and Compositions for Use of an Automatic Iniection Device
Methods and Compositions for Delivery of a Substance Using an Automatic
Injection
Device
The invention also provides methods of using the automatic injection device of
the invention for delivering a substance, e.g., medication or liquid dose of a
drug such as
a TNFoi inhibitor. In one embodiment, the automatic injection device is an
autoinjector
pen, such as a HUMIRAO pen.
Included in the methods are methods for preparing to use the automatic
injection
device, e.g., autoinjector pen, of the invention.
Use of the automatic injection device may require that a patient first choose
and
prepare an injection site. For example, methods for choosing and preparing an
injection
site for administration with an autoinjector pen, such as the FIUMIRAS pen,
include
first washing the hands of the patient thoroughly. Generally, a clean and
healthy part of
the patient's body is selected to receive the injection from the automatic
injection
device. In one embodiment, a site is chosen on the front of the patient's
thighs or
abdomen. If the abdomen is chosen, the patient should avoid the area 2 inches
around
the navel. For injection with an autoinjector pen, such as a HUMIRAO pen, a
different
CA 02950817 2016-12-07
71
site should be chosen each time an injection is given. Each new injection
should be
given at least one inch from a site used previously. Areas where the skin is
tender,
bruised, red or hard or where there are scars or stretch marks should
generally not be
used as injection sites. A patient may find it helpful tolecp notes on the
location of
previous injections.
Once an injection site is selected, the patient generally cleans the area. In
one
embodiment, the site where IIUMIRAS is to be injected is first wiped with an
alcohol
prep (swab), using a circular motion. Once cleaned, the injection site area
should not be
touched again until the patient is ready to inject.
The methods of the invention also include preparing the dose of the substance
,within the automatic injection device, e.g., autoinjector pen, to be
injected. In one
embodiment, the autoinjector pen is held with the first removable cap pointing
up. The
patient should examine the solution or substance, e.g., liquid drug, through
the windows
on the side of the automatic injection device, e.g., autoinjector pen, to make
sure, for
example, the liquid is clear and colorless. Generally, the automatic injection
device,
e.g., autoinjector pen, should not be used if the liquid is cloudy or
discolored or has
flakes or particles in it. In addition, an automatic injection device, e.g.,
autoinjector pen,
comprising adalimumab should be not used if it is frozen.
Once it has been'determined that the automatic injection device, e.g.,
autoinjector
pen, is satisfactory for use in and injection, the device may be held with the
first
removable cap pointed down. Such an action may serve to determine the level of
the
liquid drug within the automatic injection device, e.g., autoinjector pen.
In one embodiment, prior to injection, one should check to make sure that the
amount of liquid in the automatic injection device, e.g., autoinjector pen, is
the same or
close to the line visible through the window. In one embodiment, the line
represents a
full dose of the product. The top of the liquid may be curved. If the
automatic injection
device, e.g., autoinjector pen, does not have the correct amount of liquid,
the
autoinjector pen should not be used and, optionally, a pharmacist should be
called.
Injection methods for delivering a substance, such as a liquid drug, using the
automatic injection device, e.g., autoinjector pen, of the invention may
include the
following. The automatic'injection device, e.g., autoinjector pen, is held
with one hand.
With the patient's Other hand, the first removable cap is removed and
discarded. In one
embodiment, the first removable cap should be pulled straight off and/or
should not be
CA 02950817 2016-12-07
72
twisted. Following removal of the first removable cap, the patient should
check that the
needle sheath of the syringe has come off with the first removable cap. After
removal,
the interior needle cover is held in the cap. The needle housed in the syringe
barrel
should not be touched. The distal end of the stepped shroud will be exposed
following
removal of the first removable cap. The first removable cap should not be
recapped as
the needle may be damaged. In addition, the patient should take care to avoid
dropping
or crushing the automatic injection device, e.g.. autoinjector pen, as it
contains a syringe.
Following removal of the first removable cap, the second removable cap (also
referred to is'a safety cap) is removed to expose the activation button at the
top. The
patient should pull the second 'removable cap 'straight off. The second
removable cap
should not be twisted off Following removal of the first and second removable
caps,
the automatic injection device, e.g., an autoinjector pen, is now ready to
use. The patient
should be aware that the automatic injection device, e.g., an autoinjector
pen, is
activated after removing the second removable cap, and, furthermore, that
pressing the
activation button under the second removable cap will result in discharge of
medication.
The patient should also be aware that the activation button should not be
removed until
properly positioned. In addition, at this point the automatic injection
device, e.g., an
autoinjector pen, should not be recapped, as this may cause the unit to
discharge.
Once the patient is ready to deliver the injection, the automatic injection
device,
e.g.. an autoinjector pen, should be positioned so that the window is in view.
With the
patient's free hand, a sizable area of the cleaned skin may be gently squeezed
at the
injection site, Creating a platform on which to position the automatic
injection device,
e.g.. an autoinjector pen. The proximal end of the automatic injection device,
e.g., an
autoinjector pen, may be positioned the at a 90 degree angle flush against the
platform of
skin. The automatic injection device, e.g., so that it will not inject the
needle into the
patient's fingers. To begin injection, the activation button is pressed. In
one =
embodiment, the activation button is pressed using a finger, e.g., the index
finger of the
patient, to begin the injection. Alternatively, in another embodiment, the
patient may
also use a thumb to press the activation button to begin the injection. During
the
injection, the patient should try not to cover the window. In one embodiment,
when the
activation button is pressed, there will be an audible indicator, e.g. click.
The audible
indicator, e.g., click, may indicate the start of the injection. In one
embodiment, an
autoinjector pen comprising adalimumab makes noise once the activation button
is
CA 02950817 2016-12-07
73
pressed. Once the activation button is pressed, pressure should be kept on the
activation
button and the patient may continue to hold the automatic injection device,
e.g.,
autoinjector pen, with steady pressure on the injection site until the process
is finished.
In one embodiment, the process of pressing the activation button to complete
the
injection may take up to about 10 seconds. For injection, constant pressure is
maintained at the injection site for the entire period of time.
Using the automatic injection device, e.g., autoinjector pen, of the
invention, a
patient will know that the injection has finished when the indicator in the
window
appears in full view and stops. When the injection is finished, the automatic
injection
device, e.g., autoinjector pen, is pulled from the skin of the user. The
shroud will
automatically advance over the needle tip. The patient may press a cotton ball
over the
injection site and hold it, e.g., for 10 seconds. The patient should not rub
the injection
site, and should not be alarmed if there is slight bleeding. Following
injection, the
automatic injection device; e.g., autoinjector pen, should be disposed of,
such that the
patient tries not to touch the needle. The needle sleeve prevents the patient
from
touching the needle.
It should be noted that any of the instructions recited in the methods for
using the
automatic injection device of the invention may be included in a label for the
automatic
injection device, e.g., autoinjector pen, of the invention.
Methods and Compositions for Training a Recipient for Use of an Automatic
Injection
Device
Another aspect of the invention pertains to methods and compositions for
training a recipient in the use of an automatic injection device. Based on
experience in
use of the device in clinical studies, particular important features for
successful use of
the device have now been discovered and these features can be incorporated
into
business methods for training recipients in the use. of the automatic
injection device.
Such training methods, and compositions used in such methods, are beneficial
for
communicating to an end user of the device, or to a party that will introduce,
prescribe
or sell the device to an end user, important features for successful use of
the device.
Moreover, the use of a demonstration automatic injection device or trainer
device
that mimics the look and feel of the actual automatic injection device but
which is
incapable of administering the substance or medication, is particularly useful
in training
CA 02950817 2016-12-07
74
a recipient in the successful use of the actual automatic injection device,
since it allows
the recipient to experience and practice the handling and control of the
device without
the possibility of inadvertently administering the medication.
Accordingly, in one aspect, the invention provides-a method of training a
recipient on use of an automatic injection device, wherein The automatic
injection device
comprises a needle and a medication, the method comprising providing to the
recipient:
(a) a demonstration automatic injection device which lacks the needle and the
medication; and
(b) instructions for using the automatic injection device.
In another aspect, the invention provides a kit for training a recipient on
use of an
automatic injection device, wherein the automatic injection device comprises a
needle
and a medication, the kit comprising:
(a) a demonstration automatic injection device which lacks the needle and the
medication; and
(b) instructions for using the automatic injection device.
In.a preferred embodiment, the recipient is a physician that prescribes the
medication contained within the automatic injection device. In another
embodiment, the
recipient is a patient that uses the medication contained within the automatic
injection
device. Other examples of recipients include pharmacists that dispense the
automatic
injection device, family members or other caregivers of patients that use the
medication
and representatives that train physicians or patients in use of the automatic
injection
device.
In certain embodimentssof the method, including the training methods described
herein, the instructions for using the automatic injection device are conveyed
orally to
the recipient. In other preferred embodiments, instructions are conveyed in
writing (e.g.,
via a printed document) or via an audiovisual device to the recipient. In the
kits of the
invention, the instructions for using the automatic injection device typically
are
contained with a printed document or audiovisual device. Preferred audiovisual
devices
include VHS cassettes and DVDs.
=
The demonstration automatic injection device is designed to look and feel like
the actual automatic injection device, but lacks at least one component
necessary to
allow for successful administration of a medication by an end user and most
preferably
CA 02950817 2016-12-07
at least lacks a needle such that inadvertent needle pricks are avoided when
using the
demonstration automatic injection device. Preferably, the demonstration
automatic
injection device lacks both the needle and the medication that is contained in
the actual
automatic injection device.
5 In another aspect, the invention provides a method of training a
recipient on use
of an automatic injection device, wherein the automatic injection device
comprises an
activator mechanism and a medication, the method comprising conveying to the
recipient instructions to:
(a) position the automatic injection device at an injection site;
10 (h) engage the activator mechanism to begin injection of the medication;
(c) maintain engagement of the activator mechanism for a prescribed period of
time to continue injection of the medication; and
(d) remove the automatic injection device from the injection site after
passage of
the prescribed period of time.
15 The invention also provides an audiovisual device for training a
recipient on use
of an automatic injection device, wherein the automatic injection device
comprises an
activator mechanism and a medication, the audiovisual device conveying to the
recipient
instructions to:
. (a) position the automatic injection device at an injection site;
20 (b) engage the activator mechanism to begin injection of the medication;
(c) maintain engagement of the activator mechanism for a prescribed period of
time to continue injection of the medication; and
(d) remove the automatic injection device from the injection site after
passage of
the prescribed period of time.
25 Preferably, the audiovisual device is an VHS cassette or an DVD.
In the above training methods and audiovisual devices, the instructions can
further convey that initial engagement of the activator mechanism is
accompanied by an
audible sound, such as a "click". Other examples of audible sounds include a
bell, a
buzzer or a ring-tone.
30 In other embodiments of the above training methods and audiovisual
devices, the
instructions can further convey that completion of injection of the medication
is
accompanied by a visible indicator of completion and/or the instructions can
further
CA 02950817 2016-12-07
76
convey that the injection site should be sterilized prior to positioning the
automatic
injection device at the injection site
Other examples of instruction that can be conveyed in the above training
methods and audiovisual devices are described in further detail in Example 4.
In yet another aspect, the invention provides a method of training a recipient
on
use of an automatic injection device, wherein the automatic injection device
comprises
.an activator mechanism and a medication, the method comprising conveying to
the
recipient instructions to:
(a) position the automatic injection device at an injection site;
(b) engage the activator mechanism to begin injection of the medication;
(c) maintain engagement of the activator mechanism to continue injection of
the
medication until a visible indicator of completion is detected; and
(d) remove the automatic injection device from the injection site once the
visible
indicator of completion is detected.
The invention also provides an audiovisual device for training a recipient on
use
of an automatic injection device, wherein the automatic injection device
comprises an
activator mechanism and a medication, the audiovisual device conveying to the
recipient
instructions to:
(a) position the automatic injection device at an injection site;
(b) engage the activator mechanism to begin injection of the medication;
(c) maintain engagement of the activator mechanism to continue injection of
the
medication until a visible indicator of completion is detected; and
(d) remove the automatic injection device from the injection'site once the
visible
indicator of completion is detected.
Preferably, the automatic injection device comprises an indicator window and
the
visible indicator of completion comprises a color indicator appearing in the
indicator
window. A preferred color indicator is a yellow color indicator. Other
examples of
suitable color indicators include red, orange, blue, green, pink or purple
color indicators.
Other examples of visible indicators of completion include the appearance of a
symbol
or design in an indicator window upon completion of injection and appearance
of a
"pop-up" button on the automatic injection device upon completion of
injection.
In other embodiments of the above training methods and audiovisual devices,
the
instructions can further convey that engagement of the activator mechanism
should be
CA 02950817 2016-12-07
77
maintained for a prescribed period of time to continue injection of the
medication and/or
the instructions can further convey that the injection site should be
sterilized prior to
positioning the automatic injection devite at the injection site. Preferably
the prescribed
period of time is 10 seconds. Another preferred prescribed period of time is
at least 10
seconds. In various other embOdiments, the prescriked period of time is I
second, 2
seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8.seconds, 9
seconds, 11
seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds, 30 seconds, 45
seconds or I
minute.
In another embodiment of the above training methods and audiovisual devices,
the instructions further convey that the automatic injection device should be
examined
for proper dosage and formulation of the medication prior to positioning the
automatic
injection device at the injection site Such examination can be done, for
example, by
looking at the medication-through a window present in the automatic injection
device
that 'allows for visualization of the liquid medication contained in the
device. Examples
of examination for proper dosage and formulation include examining whether the
medication is clear and colorless (e.g., is not cloudy and does not contain
particulate
matter) and examining whether the level of medication is the same as or close
to a."fill-
line" indication visible in the window. =
Other examples of instruction that can be conveyed in the above training
methods and audiovisual devices are described in further detail in Example 4.
VII. Methods and Compositions for Promoting, Use of an Automatic Injection
Device
One aspect of the invention pertains to methods and compositions for promoting
the use of an automatic injection device. Based on the results of clinical
studies,
advantageous features of an automatic injection device have now been
discovered and
these features can be incorporated into business methods for promoting the use
of the
automatic injection device. Such promotional methods, and compositions used in
such
methods, are beneficial for communicating to an end user of the device, or to
a party that
will introduce, prescribe or sell the device to an end user, the advantageous
features of
the device.
Accordingly, in one aspect, the invention provides a method of promoting an
automatic injection device comprising a.substance, such as a medication, to a
recipient,
CA 02950817 2016-12-07
78
the method comprising conveying to the recipient at least one message selected
from the
group consisting of:
(a) the automatic injection device is less painful for a patient to use than
a pre-filled syringe;
(b) the automatic injection device is preferred for use by patients as
compared to a pre-filled syringe;
(c) the automatic injection device is easier to use by a patient than a pre-
filled syringe;
(d) the automatic injection device is more convenient for a patient to use
than a pre-filled syringe; .
(e) the automatic injection device reduces anxiety of patients with a fear
of needles, as compared to a pre-filled syringe, since the needle is not
visible in the
device; and
(f) the automatic injection device is designed to be easy to use from initial
' use of the device.
In a preferred embodiment, the message that the automatic injection device is
less painful for a patient to use than a pre-filled syringe is conveyed to the
recipient. For
example, a message that 80% of patients in a clinical trial rated the
automatic injection
device as less painful than a pre-filled syringe can be conveyed to the
recipient.
= In another preferred embodiment, the message that the automatic injection
device
is preferred for use by patients as compared to a pre-filled syringe is
conveyed to the
recipient. For example, a message that 90% of patients in a clinical trial
preferred the
automatic injection device to a pre-filled syringe can be conveyed to the
recipient.
Particular structural features of the automatic injection device also'can be
conveyed to the recipient. For example, a message that the automatic injection
device
comprises a five- bevel needle, as compared to a three-bevel needle for a pre-
filled
syringe, additionally can be conveyed to the recipient. As another example, a
message
that the needle is not visible in the device (L e., not visible to the user of
the device when
the device is used as instructed) can be conveyed to the recipient.
In a preferred embodiment, the recipient is a physician that prescribes the
medication contained within the automatic injection device. In another
embodiment, the
recipient is a patient that uses the medication contained within the automatic
injection
device. Other examples of recipients include pharmacists that dispense the
automatic
CA 02950817 2016-12-07
79
injection device, family members or caretakers thereof, of patients that use
the
medication and representatives that train physicians or patients in use of the
automatic
injection device.
= In a preferred embodiment, the at least one message is conveyed orally to
the
recipient. In another preferred embodiment, the at least one message is
conveyed in
writing to said recipient (e.g., via a printed document, such as a package
insert). In yet
another preferred embodiment, the at least one message is conveyed to the
recipient via
an audiovisual device.
In another 'aspect, the invention provides an audiovisual device for promoting
an
automatic injection device Comprising a medication to a recipient, wherein the
device
conveys to the recipient at least one message selected from the group
consisting of:
(a) the automatic injection device is less painful for a patient to use than
a pre-filled syringe;
(b) the automatic injection device is preferred for use by patients as
compared to a pre-filled syringe;
(c) the automatic injection device is easier to use by a patient than a pre-
filled syringe;
.(d) the automatic injection device is more convenient for a patient to use
than a pre-filled syringe;
(e) the automatic injection device reduces anxiety of patients with a fear
of needles, as compared to a pre-filled syringe, since the needle is not
visible in the
device; and
(f) the -autornatic.injection device is designed to be easy to use
ftbm:initial
use
of the device.
In a preferred embodiment, the audiovisual device is a Video Home System
(VHS) cassette. In another preferred embodiment, the audiovisual device is a
Digital
Video Disc (DVD).
In a preferred embodiment, the audiovisual device conveys the message that the
automatic injection device is less painful for a patient to use than a pre-
filled syringe.
For example, the audiovisual device can convey a message that 80% of patients
in a
clinical trial rated the automatic injection device as less painful than a pre-
filled syringe.
CA 02950817 2016-12-07
In another preferred embodiment, the audiovisual device conveys the message
that the automatic injection device is preferred for use by patients as
compared to a pre-
filled syringe. For example, the audiovisual device can convey a message that
90% of
patients in a clinical trial preferred the automatic injection device to a pre-
filled syringe.
5 The audiovisual device also can convey particular structural features of
the
automatic injection device to the recipient. For example, the audiovisual
device can
convey a message that the automatic injection device comprises a five-bevel
needle, as
compared to a three- bevel needle for a pre-filled syringe. As another
example, the
audiovisual device can convey a message that the needle is not visible in the
device (Le.,
10 not visible to the user of the device when the device is used as
instructed).
In still other embodiments, an automatic injection device previously described
in
the art is used in the methods and compositions of the invention relating to
training and
promoting an automatic injection device. Suitable automatic injection devices
have
been described in the art, including but not limited to the devices described
in U.S.
15 Patent Nos. 3,941,130; 4,261,358; 5,085,642; 5,092,843; 5,102,393;
5,267,963;
6,149,626; 6,270,479; and 6,371,939.
VII. Disorders In Which TNFa Activity Is Detrimental Which Can Be Treated
With a
TNFa lubbitor Using an Automatic Injection Device
20 The automatic injection device, e.g., autoinjector pen, of the invention
may be
used in methods of treating disorders, including, in one embodiment; disorders
associated with detrimental TNF activity. In one embodiment, the automatic
injection
device, e.g., autoinjector pen, is used to deliver a substance, e.g., a TNFa
inhibitor, to a
patient for treatment, wherein the disorder includes, but not limited to,
rheumatoid
25 arthritis (including juvenile arthritis), Crohn's disease, psoriasis,
psoriatic arthritis, and
ankylosmg spondylitis.
. .
As used herein, the term "a disorder in which TNFcc activity is detrimental"
is
intended to include diseases and other disorders in which the presence of TNFa
in a
patient suffering from the disorder has been shown to be or is suspected of
being either
30 responsible for the pathophysiology of the disorder or a factor that
contributes to a
worsening of the disorder. Accordingly, a disorder in which TNFcc activity is
detrimental is a disorder in which inhibition of TNFa activity is expected to
alleviate the
symptoms and/or progression of the disorder. Such disorders may be evidenced,
for
CA 02950817 2016-12-07
81
exaniple, by an increase in the Concentration of TNFa in a biological fluid of
a patient
suffering from the disorder (e.g., an increase in the concentration of TNFa in
serum,
plasma, synovial fluid, etc. of the patient), which can be detected, for
example, using an
anti-TNFa antibody as described above. There are numerous examples of
disorders in
which TNFa activity is detrimental which are discussed further below:
A. Autoimmune Diseases
Tumor necrosis factor has been implicated in playing a role in the
pathophysiology of a variety of autoimmune diseases. For example, TNFa has
been
implicated in activating tissue inflammation and causing joint destruction in
rheumatoid
arthritis (see e.g., Moeller, A., etal. (1990) Cytokine 2:162-169; U.S. Patent
No.
5,231,024 to Moeller etal.; European Patent Publication No. 260 610 BI by
Moeller,
A.; Tracey and Cerami, supra; Arend, W.P. and Dayer, J-M. (1995) Atilt Rheum.
38:151-160; Fava, R.A., et al. (1993) Clin. Exp. Immunol. 94:261-266). TNFa
also has
=been implicated in promoting the death of islet cells and in mediating
insulin resistance
in diabetes (see e.g., Tracey and Cerami, supra; PCT Publication No. WO
94/08609).
TNFa also has been implicated in mediating cytotoxicity to oligodendrocytes
and
induction of inflammatory plaques in multiple sclerosis (see e.g., Tracey and
Cerami,
supra). TNFot also has been implicated in mediating cytotoxicity to
oligodendrocytes
and induction of inflammatory plaques in multiple sclerosis (see e.g., Tracey
and
Cerami, supra). Chimeric and humanized murine anti-hTNFa antibodies have
undergone clinical testing for treatment of rheumatoid arthritis (see e.g.,
Elliott, M.J., et
al. (1994) Lancet 344:1 I 25-1127; Elliot, Mi., etal. (1994) Lancet 344:1105-
1110;
Rankin, E.C., et al. (1995) Br. J. Rheumatol. 34:334-342).
TNFcc antibodies, such as adalimumab, may be used to treat autoimmune
diseases, in particular those associated with inflammation. Examples of such
=
autoimmune Conditions include rheumatoid arthritis, rheumatoid spondylitis,
. .
osteoarthritis and gouty arthritis, allergy, multiple sclerosis, autoimmune
diabetes,
autoimmune uveitis and nephrotic syndrome. Other examples of autoimmune
conditions
include multisystem autoimmune diseases and autoimmune hearing loss.
In one embodiment of the invention, a TN% inhibitor is used to treat
autoimmune disorders such as lupus. Lupus is has been shown lobe associated
with
"INF activity (Shvidel et al. (2002) Hematol J. 3:32; Studnicka-Benke et al.
(1996) Br J
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82
Rheumatol. 35:1067). The term "lupus" as used herein refers to a chronic,
inflammatory
autoimmune disorder called lupus erythematosus that may affect many organ
systems
including the skin, joints and internal organs. Lupus is a general tem which
includes a
number of specific types of lupus, including systemic lupus, lupus nephritis,
and lupus
cere.britis. In systemic lupus (SLE), tlie.body's natural defenses are turned
against the
=.. .
body and rogue immune cells attack the body's tissues. -Antibodies may be
produced
that can react against the body's blood cells, organs, and tissues. This
reaction leads to
immune cells attacking the affected systems, producing a chronic disease.
Lupus
nephritis, also referred to as lupus glomerular disease, is kidney disorder
that is usually a
complication of SLE, and is characterized by damage to the glomerulus and
progressive
loss of kidney function. Lupus cerebritis refers to another complication of
SLE, which
is inflammation of the brain and/or central nervous system.
Another autoimmune disease which can be treated using a TNFa antibody is
Crohn's disease, which is described in more detail below in the Intestinal
Disorders
Section.
13. Intestinal Disorders
Tumor necrosis factor has been implicated in the pathophysiology of
inflammatory bowel disorders including Crohn's disease (see e.g., Tracy el a
(1986)
Science 234:470; Sun et al. (1988) J. Clirt. Invest. 81:1328; MacDonald etal.
(1990)
Clin. Exp. Immunol. 81:301). Chimeric murine anti-hTNFa antibodies have
undergone
clinical testing for treatment of Crohn's disease (van Dullemen et al. (1995)
Gastroenterology 109:129). The invention includes treatment comprising
administering
a TNFa antibody obtained using the method of the invention to treat intestinal
disorders,
such as idiopathic inflammatory bowel disease, using human antibodies, or
antigen-
binding fragments thereof. Idiopathic inflammatory bowel disease includes two
syndromes, Crohn's disease and ulcerative colitis. In one embodiment, an
antibody
obtained using the method of the invention is also used to treat disorders
often
associated with IBD and Crohn's disease. The term "inflammatory bowel disorder
(IBD)-related disorder" or "Crohn's disease-related disorder," as used
interchangeably
herein, is used to describe conditions and complications commonly associated
with IBD
and Crohn's disease.
CA 02950817 2016-12-07
83
The invention also includes a multiple-variable dose regimen comprising
administering a TNFot antibody to treat Cretin's disease. The treatment of
Crohn's
disease is based on location, extent, and severity of disease. Phannacologic
interventions
include anti-inflammatory agents (aminosalicylates and corticosteroids) and
inununomodulatory agents (azathioprine and 6-mercaptopurine [6-MP],
cyclosporine,
methotrexate [MTX], antibiotic agents, and biologic agents).C-reactive protein
(CRP)
and erythrocyte sedimentation rate (ESR) levels reflect non-specific acute
phase
reactions. Endoscopy is a primary means of diagnosing Crohn's disease.
Radiologic
features of Crohn's disease are shown by barium examination includes mucosa!
edema,
aphthous and linear ulcerations, asymmetrical narrowing and strictures, and
separation
of adjacent loops of bowel caused by mesenteric thickening. Abnormalities are
focal and
asymmetric. The primary histologic lesion is an aphthous ulcer. Subjects with
Crohn's
disease can be evaluated using the Cretin's Disease Activity Index (CDAI),
which is a
standard measure of the severity of the disease with higher scores indicating
more severe
disease activity.
Examples of Crohn's disease-related disorders that can be treated using the
methods of the invention include fistula t in the bladder, vagina, and skin;
bowel
obstructions; abscesses; nutritional deficiencies; complications from
corticosteroid use;
inflammation of the joints; erythem nodosum; pyoderma gangrenosum; and lesions
of
the eye. Other disorders commonly associated with Crohn's disease include
Crohn's.
related artlualgias, fistulizing Crohn's, indeterminant colitis, and
pouchitis.
=
C. .pondyloarthr'opathies = = ' = - = = = = =
= TNFct has been implicated in the pathophysiologY of a Wide variety of
disorders,
including inflammatory diseases such as spondyloarthopathies (see e.g.,
Moeller et aL
(1990) Cytokine 2:162; U.S. Patent No. 5,231,024; European Patent Publication
No. 260
610). The invention provides multiple-variable dose methods for inhibiting
TNFa
activity in a patient suffering from a spondyloarthropathy, which method
comprises
administering to the patient an antibody, antibody portion, such that TNFoz
activity in
' the patient suffering from a spondyloarthropathy is inhibited.
As used herein, the term "spondyloarthropathy" or "spondyloarthropathies" is
used to refer to .any one of several diseases affecting the joints of the
spine, wherein such
diseases share common clinical, radiological, and histological features. A
number of
CA 02950817 2016-12-07
84
spondyloarthropathies share genetic characteristics, i.e. they are associated
with the
HLA-1327 allele. In one embodiment, the term spondyloarthropathy is used to
refer to
any one of several diseases affecting the joints of the spine, excluding
ankylosing
spondylitis, wherein such diseases share common clinical, radiological, and
histological
features. Examples of spondyloarthropathies include ankylosing spondylitis,
psoriatie
arthritis/spondylitis, enteropathic arthritis, reactive arthritis or Reiter's
syndrome, and
undifferentiated spondyloarthropathies. Examples of animal models used to
study
spondyloarthropathies include an/clank transgenic mice, HLA-B27 transgenic
rats (see
Taurog et al. (1998) The Spondylarthritides. Oxford:Oxford University Press).
The automatic injection device of the invention can also be used to treat
patients
who are at risk of developing a spondyloarthropathy using multiple-variable
dose
methods. Examples of patients who are at risk of having spondyloarthropathies
include
humans suffering from arthritis. Spondyloarthropathies can be associated with
other
forms of arthritis, including rheumatoid arthritis. In one embodiment of the
invention;
antibodies are used in multiple-variable dose methods to treat a patient who
suffers from
a spondyloarthropathy associated with rheumatoid arthritis. Examples of
spondyloarthropathies that can be treated with a TNFa antibody are described
below:
I. Ankylosing Spondylitis (AS)
Tumor necrosis factor has been implicated in the pathophysiology of ankylosing
spondylitis (see Verjans et al. (1991)Arthritis Rheum. 34:486; Verjans et aL
(1994) Clin
Exp Immunol. 97:45; Kaijtzel et al. (1999) Hum Immunol. 60:140). Ankylosing
spondylitis (AS) is an inflammatory disorder involving inflammation of one or
more
vertebrae. AS is a chronic inflammatory disease that affects the axial
skeleton and/or
peripheral joints, including joints between the vertebrae of the spine and
sacroiliac joints
and the joints between the spine and the pelvis. AS can eventually cause the
affected
vertebrae to fuse or grow together. Spondyarthropathies, including AS, can be
associated with psoriatic arthritis (PsA) and/or inflammatory bowel disease
(IBD),
including uleerative colitis axiszl Crohn's 'disease. =
== Early manifestations of AS can be determined by radiographic tests,
including
CT scans and MRI scans. Early manifestations of AS often include scroiliitis
and
changes in the sacroliac joints as evidenced by the blurring of the cortical
margins of the
subchrondral bone, followed by erosions and sclerosis. Fatigue has also been
noted as a
CA 02950817 2016-12-07
common symptom of AS (Duffy et al. (2002)ACR 66th Annual Sciengfic Meeting
Abstract). Accordingly, multiple-variable dose methods comprising
administering an
antibody, or antigen-binding fragment thereof, of the invention can be used to
treat AS.
In one embodiment, the multiple-variable dose method of the invention is used
to
5 treat a spondyloarthropathy associated with IBD, including AS. AS is
often treated with
nonsteroidal anti,inflamniatory medications (NSA1Ds), such as aspirin or
indomethacin.
Accordingly, a TNFa antibody used in the multiple-variable dose method of the
invention may also be administered in combination with agents commonly used to
reduce inflammation and pain commonly associated with ankylosing spondylitis.
2. Psoriatic arthritis
Tumor necrosis factor has been implicated in the pathophysiology of psoriatic
arthritis (PsA) (Partsch et at. (1998) Ann Rheum Dis. 57:691; Ritchlin etal.
(1998)J
Rheumatol. 25:1544). As referred to herein, psoriatic arthritis or psoriasis
associated
with the skin, refers to chronic inflammatory arthritis which is associated
with psoriasis,
which is a common chronic skin condition that causes red patches on the body.
About 1
in 20 individuals with psoriasis will develop arthritis along with the skin
condition, and
in about 75% of cases, psoriasis precedes the arthritis. PsA exhibits itself
in a variety of
ways, ranging from mild to severe arthritis, wherein the arthritis usually
affects the
fingefs'and the spine. When the spine is affected, the symptoms are similar to
those of
ankylosing spondylitis, as described above. The TNFa'antibody, or antigen-
binding
fragment thereof, obtained using the invention can be used for treatment of
PsA.
PsA is sometimes associated with arthritis mutilans. Arthritis mutilans refers
to a
disorder that is characterized by excessive bone erosion resulting in a gross,
erosive
deformity that mutilates the joint. In one embodiment, antibodies obtained
using the
method of the invention are used to treat arthritis mutilans.
3. Reactive arthritis / Reiter's syndrome
Tumor necrosis factor has been implicated in the pathophysiology of reactive
arthritis, which is also referred to as Reiter's syndrome (Braun etal. (1999)
Arthritis
Rheum. 42(10):2039). Reactive arthritis (ReA) refers to arthritis that
complicates an
infection elsewhere in the body, often following enteric or urogenital
infections. ReA is
often characterized by certain clinical symptoms, including inflammation of
the joints.
CA 02950817 2016-12-07
86
(arthritis), urethritis, conjunctivitis, and lesions of the skin and mucous
membranes. In
addition, ReA can occurs following infection with a sexually transmitted
disease or
dysenteric infection, including chlainydia, campylobacter, salmonella, or
yersinia.
Accordingly, antibodies obtained using the method of the invention may be used
to treat
ReA.
4. Undifferentiated spondyloarthropathies
' In one embodiment, antibodies obtained using methods of the invention
are used
to treat patients suffering from undifferentiated spondyloarthropathies (see
Zeidler et al.
(102) Rheum Dis Clin North Am. 18:187). Other terms used to describe
undifferentiated spondyloarthropathies include seronegative oligoarthritis and
undifferentiated oligoarthritis. Undifferentiated spondyloarthropathies, as
used herein,
refers to a disorder wherein the patient demonstrates only some of the
symptoms
assOciated with a spondyloarthropathy. This condition is usually observed in
young
adults who do not have 1I3D, psoriasis, or the classic symptoms of AS or
Reiter's
syndrome. In some instances, undifferentiated spondyloarthropathies may be an
early
indication of AS. In one embodiment, the invention comprises administering a
TNFa
antibody, or antigen-binding fragment thereof, obtained using the claimed
process to
treat undifferentiated spondyloarthropathies.
D. Skin and Nail Disorders
Tumor necrosis factor has been implicated in the pathophysiology of skin and
nail disorders. The term "skin disorder" or "skin disease" as used
interchangeably
herein; refers to abnormalities, other than injury wounds, of the skin that
have induced a
strife of inflammation. In one embodiment, the skin disorder of the invention
is an
inflammatory skin disorder, wherein the skin is characterized by capillary
dilatation,
leukocytic infiltration, redness, heat, and/or pain. Examples of skin
disorders include,
but are not limited to, psoriasis, pemphigus vulgaris, scleroderma, atopic
dermatitis,
sarcoidosis, erythema nodosum, hidradenitis suppurative, lichen planus,
Sweet's
syndrOme, and vitiligo. As used herein, the term "skin and nail disorder in
which TNFx
activity is detrimental" is intended to include skin and/or nail disorders and
other
disorders in which the presence of 'INFct in a patient suffering from the
disorder has
been shown to be or is suspected of being either responsible for the
pathophysiology of
CA 02950817 2016-12-07
87
the disorder or a factor that contributes to a worsening of the disorder,
e.g., psoriasis.
Accordingly, skin, and nail disorders in which TNFa activity is detrimental
are disorders
in which inhibition of TIµIFec activity is expected to alleviate the symptoms
and/or
progression of the disorder. The use of the antibodies, antibody portions, and
other
TNFet inhibitors of the invention in the treatment of specific skin and nail
disorders is
discussed further below. In certain embodiments, the treatment method of the
invention
is performed in combination with another therapeutic agent, as described
below. In one
embodiment, the antibodies obtained using the method of the invention
comprising
administering a TNFcc antibody in combination with another therapeutic agent
is used
for the treatment of psoriasis and the treatment of psoriasis associated with
arthritis.
1. Psoriasis
Tumor necrosis factor has been implicated in the pathophysiology of psoriasis
(Takematsu et al. (1989) Arch Dermatol Res. 281:398; Victor and Gottlieb
(2002)J
Drugs Dermatol. 1:264). The term "psoriasis" as used herein, refers to skin
disorders
associated with epidermal hyperplasia. Examples of psoriasis include, but are
not
limited to, chronic plaque psoriasis, guttate psoriasis, inverse psoriasis,
pustular
psoriasis, psoriasis vulgaris, and erythrOdermic psoriasis. Psoriasis can also
be
associated with other inflammatory disorders, including inflammatory bowel
disease
(1BD) and rheumatoid arthritis (RA).
Psoriasis is described as a skin inflammation (irritation and redness)
characterized by frequent episodes of redness, itching, and thick, dry,
silvery scales on
the skin. In particular, lesions are formed which involve primary and
secondary
alterations in epidermal proliferation, inflammatory responses of the skin,
and an
expression of regulatory molecules such as lymphokines and inflammatory
factors.
Psoriatic skin is morphologically characterized by an increased turnover of
epidermal
cells, thickened epidermis, abnormal keratinization, inflammatory cell
infiltrates into the
epidermis and polymorphonuclear leukotyte and lymphocyte infiltration into the
epidermis layer resulting in an increase in the basal cell cycle. Psoriasis
often involves
the hails, which frequently exhibit pitting, separation of the nail,
thickening, and
discoloration. Psoriasis is often associated with other inflammatory
disorders, for
example arthritis, including rheumatoid arthritis, inflammatory bowel disease
(IBD), and
Crohn's disease. Approximately one thrid of patients with psoriasis also have
psoriatic
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arthritis (PsA) which, as described above, causes stiffness, swelling of the
joints, pain,
and reducd range of motion (Greaves etal. (1995)N. Eng. J. Med. 332:581).
Evidence of psoriasis is most commonly seen on the trunk, elbows, knees,
scalp,
skin folds, or fingernails, but it may affect any or all parts of the skin.
Normally, it takes
about a month for new skin cells to move up from the lower layers to the
surface. In
psoriasis, this process takes only a few days, resulting in a build-up of dead
skin cells
= = ; . = . = = . . -
and formation of thick scales. Symptoms of psoriasis include: skin patches,
that are dry
or red, covered with silvery scales, raised patches of skin, accompanied by
red borders,
that may crack and become painful, and that are usually located on the elbows,
knees,
trunk, scalp, and hands; skin lesions, including pustules, cracking of the
skin, and skin
redness; joint pain or aching which may be associated with of arthritis, e.g.,
psoriatic
arthritis.
Treatment for psoriasis often includes a topical corticosteroids, vitamin D
analogs, and topical or oral retinoids, or combinations thereof. In one
embodiment, the
TNFcc antibody of the invention is administered in combination with or the
presence of
one of these common treatments. Additional therapeutic agents that can be
combined
with the TNFa antibody obtained using the methods of the invention for
treatment of
psoriasis are described in more detail below.
The diagnosis of psoriasis is nsually,based on the appearance of the skin.
Additionally a skin biopsy, or scraping and culture of skin patches may be
needed to rule
out other skin. 'disorders. = An x:ray maybe used to check for psoriatic
arthritis-if joint
pain is present and persistent.
= Improvements in psoriasis in a patient can be monitored by the patient's
Psoriasis
Area and Severity Index Score (PASI). The method for determining the PASI has
been
described in Fredriksson and Pettersson (1978) Dermatologica 157:238 and Marks
etal.
(1989) Arch Dermaiol 125:235. Briefly, the index is based on evaluation of
four
anatomic sites, including the head, upper extremities, trunk, and lower
extremities, for
erythema, induration, and desquamation using a 5 point scale (0= no symptoms;
1=slight; 2= moderate; 3=marked; 4=very marked). Based on the extent of
lesions in a
given anatomic site, the area affected is assigned a numerical value (0=0; 1
<10%; 2 =
10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70=89%; 6 = 90-100%). The PASI score is
then
calculated, wherein the possible range of PASI score is 0.0 to 72.0 with the
highest score
representing complete erythroderma of the severest degree. = =
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89
In one embodiment of the invention, a TNFa antibody is used for the treatment
of psoriasis, including chronic plaque psoriasis, guttate psoriasis, inverse
psoriasis,
pustular psoriasis, pemphigus vulgaris, erythrodermic psoriasis, psoriasis
associated
with inflammatory bowel disease (IBD), and psoriasis associated with
rheumatoid
arthritis (RA). In another embodiment, a TNFa antibody, such as adalimumab, is
used
to treat patients who have .psoriasis in combination with PsA. Specific types
of psoriasis
included in the treatment methods of the.invention are described in detail
below:
a. Chronic plaque psoriasis
Tumor necrosisTactor has been iniplicated in the pathophysiology of chronic
plaque psoriasis (Asadullah etal. (1999) Br J Dermaio1.141:94). Chronic plaque
psoriasis (also referred to as psoriasis vulgaris) is the most common form of
psoriasis.
Chronic plaque psoriasis is characterized by raised reddened patches of skin,
ranging
from coin-sized to much larger. In chronic plaque psoriasis, the plaques may
be single
or multiple, they may vary in size from a few millimeters to several
centimeters. The
plaques are usually red with a scaly surface, and reflect light when gently
scratched,
creating a "silvery" effect. Lesions (which are often symmetrical) from
chronic plaque
psoriasis occur all over body, but with predilection for extensor surfaces,
including the
knees; elbows, lumbosacral regions, scalp, and nails. Occasionally chronic
plaque
psoriasis can occur on the penis, vulva and flexures, but scaling is usually
absent.
Diagnosis of patients with chronic plaque psoriasis is usually based on the
clinical
features described above. In particular, the distribution, color and typical
silvery scaling
of the lesion in chronic plaque psoriasis are characteristic of chronic plaque
psoriasis.
b. GuItate psoriasis
Guttate psoriasis refers to a form of psoriasis with characteristic water drop
shaped scaly plaques. Flares of guttate psoriasis generally follow an
infection, most
notably a streptococcal throat infection. Diagnosis of guttate psoriasis is
usually based
on the appearance of the skin, and the fact that there is often a history of
recent sore
throat.
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c. Inverse psoriasis
Inverse psoriasis is a form of psoriasis in which the patient has smooth,
usually
moist areas of skin that are red and inflammed, which is unlike the scaling
associated
with plaque psoriasis. Inverse psoriasis is also referred to as intertiginous
psoriasis or
5 flexural psoriasis. Inverse Psoriasis occurs mostly in the armpits,
groin, under the
breasts and in other skin folds around the genitals and buttocks, and, as a
result of the
locations of presentation, rubbing and sweating can irriate the affected
areas.
d. Pustular psoriasis
10 Pustular psoriasis, also referred to as palmar plantar psoriasis, is
a form of
psoriasis that causes pus-filled blisters that vary in size and location, but
often occur on
the hands and feet. The blisters may be localized, or spread over large areas
of the body.
Pustular psoriasis can be both tender and painful, can cause fevers.
15 e. Other psoriasis disorders
' Other examples of psoriatic disorders that can be treated with a
TNFct antibody
delfvered Using the methods of the invention include eiythrodentic pstiriasis,
vulgaris,
psoriasis associated with IBD, and psoriasis associated with arthritis,
including
rheumatoid arthritis.
2. Pemphigus vulgaris
Pemphigus vulgaris is a serious autoimmune systemic dermatologic disease that
often affects the oral mucous membrane and skin. The pathogenesis of pemphigus
vulgaris is thought to be an autoimmune process that is directed at skin and
oral mucous
membrane desmosomes. Consequentially, cells do not adhere to each other. The
disorder manifests as large fluid-filled, rupture-prone bullae, and has a
distinctive
histologic appearance. Anti-inflammatory agents are the only effective therapy
for this
disease that has a high mortality rate. Complications that arise in patients
suffering
from pemphigus vulgaris are intractable pain, interference with nutrition and
fluid loss,
and infections:
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91
3. Alopic dermatitis / eczema
Atopic dermatitis (also referred to as eczema) is a chronic skin disorder
categorized by scaly and itching plaques. People with eczema often have a
family
history of allergic conditions like asthma, hay fever, or eczema. Atopic
dermatitis is a
hypersensitivity reaction (similar to an allergy) which occurs in the skin,
causing chronic
inflammation..The inflammation causes the skin to become itchy and scaly.
Chronic
irritation and scratching can cause the skin to thicken and become leathery-
textured.
Exposure to environmental irritants can worsen symptoms, as can dryness of the
skin,
exposure to water, temperature changes, and stress.
Subjects with atopic dermatitis can be identified by certain symptoms, which
often include intense itching, blisters with oozing and crusting, skin redness
or
inflammation around the blisters, rash, dry, leathery skin areas, raw areas of
the skin
from scratching, and ear discharges/bleeding.
4. Sarcoidosis
Sarcoidosis is a disease in which granulomatous inflammation occurs in the
lymph nodes, lungs, liver, eyes, skin, and/or other tissues. Sarcoidosis
includes
cutaneous sarcoidosis (sarcoidosis of the skin) and nodular sarcoidosis
(sarcoidosis of
the lymph nodes). Patients with sarcoidosis can be identified by the symptoms,
which
often include general discomfort, uneasiness, or an ill feeling; fever; skin
lesions.
5. Erythema nodosum
Erythema nodosum refers to an inflammatory disorder that is characterized by
tender, red nodules under the skin, typically on the anterior lower legs.
Lesions
associated with erythema nodosum often begin as flat, but firm, hot red
painful lumps
(approximately an inch across). Within a few days the lesions may become
purplish,
and then over several weeks fade to a brOwnish flat patch.
In some instances, erythema nodosum may be associated with infections
including, streptococcus, coccidioidomyeosis, tuberculosis, hepatitis B,
syphilis, cat
scratch disease, tularemia, yersinia, leptospirosis psittacosis,
histoplasmosis,
mononucleosis (EBV). In other instances, erythema nodosum may be associated
with
sensitivity to certain medications including, oralcontraceptives, penicillin,
sulfonamides,
sulfones, barbiturates, hydantoin, phenacetin, salicylates, iodides, and
progestin.
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Erythema nodosum is often associated with other disorders including, leukemia,
sarcoidosis, rheumatic fever, and ulcerative colitis.
Symptoms of erythema nodosurn usually present themselves on the shins, but
lesions may also occur on other areas of the body, including the buttocks,
calves, ankles,
thighs and upper extremities. Other symptoms in patients with erythema nodosum
can
include fever and malaise.
= = 6. Hidradenitis suppurative
= Hidradenitis suppurativa refers to a skin disorder in which swollen,
painful,
inflamed lesions or lumps develop in the groin and sometimes under the arms
and under
the breasts. Hidradenitis suppurativa occurs when apocrine gland outlets
become
blocked by perspiration or are unable to drain normally because of incomplete
gland'
=
development. Secretions trapped in the glands force perspiration and bacteria
into
surrounding tissue, causing subcutaneous induration, inflammation, and
infection.
Hidradenitis suppurativa is confined to areas of the body that contain
apocrine glands.
These areas are the axillae, areola of the nipple, groin, perineum,
circumanal, and
periumbilical regions.
7. Lichen planus
Tumor necrosis factor has been implicated in the pathophysiology of lichen
planus (Sklavounou et al. (2000)J Oral Pathol Med. 29:370). Lichen planus
refers to a
disorder of the skin and the mucous membranes resulting in inflammation,
itching, and
distinctive skin lesions. Lichen planus may be associated with hepatitis C or
certain
medications.
8. Sweet's syndrome
Inflammatory cytokines, including tumor necrosis factor, have been implicated
in
the pathophysiology of Sweet's syndrome (Reuss-Borst et al. (1993) Br or
Haematol.
84:356). Sweet's syndrome, which was described by R.D. Sweet in 1964, is
characterized by the sudden onset of fever, leukocytosis, and cutaneous
eruption. The
eruption consists of tender, erythematous, well-demarcated papules and plaques
which
show dense neutrophilic infiltrates microscopically. The lesions may appear
anywhere,
but favor the upper body including the face. The individual lesions are often
described as
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pseudovesicular or pseudopustular, but may be frankly pustular, bullous, or
ulcerative.
Oral and eye involvement (conjunctivitis or episcleritis) have also been
frequently
reported in patients with Sweet's syndrome. Leukemia has also been associated
with
Sweet's syndrome.
9. Vitiligo
Vitiligo refers to a skin condition in which there is loss of pigment from
areas of
skin resulting in irregular white patches with normal skin texture. Lesions
characteristic
of vitiligo appear as flat depigmented areas. The edges of the lesions are
sharply defined
but irregular. Frequently affected areas in patients with vitiligo include the
face, elbows
and knees, hands and feet, and genitalia.
10. Scleroderma
Tumor necrosis factor has been implicated in the pathophysiology of
scleroderma (Tutuncu et al. (2002) Clin Exp Rheumatot 20(6 Suppl 28):S146;
Mackiewicz et aL (2003) Clin Exp RheumatoL 21:41; Murota et aL (2003)
Arthritis
Rheum. 48:1117). Scleroderma refers to a a diffuse connective tissue disease
characterized by changes in the skin, blood vessels, skeletal muscles, and
internal
organs. Scleroderma is also referred to as CREST syndrome or progressive
systemic
sclerosis, and usually affects people between the ages 30-50. Women are
affected more
often than men.
= The cause of scleroderma is unknown. The disease may produce local or
systemic symptoms. The course and severity of the disease varies widely in
those
affected.Excess collagen deposits in the skin and other organs produce the
symptoms.
Damage to small blood vessels within the skin and affected organs also occurs.
In the
skin, ulceration, calcification, and changes in pigmentation may occur.
Systemic
features may include fibrosis and degeneration of the heart, lungs, kidneys
and
gastrointestinal tract.
== Patients suffering from scleroderma exhibit certain clinical
features, including,
blanching, blueness, or redness of fingers and toes in response to heat arid
cold
(Raynaud's phenomenon), pain, stiffness, and swelling of fingers and joints,
skin
thickening and shiny hands and forearm, esophageal reflux or heartburn,
difficulty
swallowing, and shortness of breath. Other clinical sypmtoms used to diagnose
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94
scleroderma include, an elevated erythrocyte sedimentaion rate (ESR), an
elevated
rheumatoid factor (RF), a positive antinuclear antibody test, urinalysis that
shows
protein and microscopic blood, a chest X-ray that may show fibrosis, and
pulmonary
funtion studies that show restricitive lung disease.
11. Nail disorders
Nail disorders include any abnormality of the nail. The term "nail disorder"
or
"nail disease" as used herein, refers to conditions wherein the fingernails or
toenails to
abnormal color, shape, texture, or thickness. Specific nail disorders include,
but are not
limited to, pitting, koilonychia, Beau's lines, spoon nails, onycholysis,
yellow nails,
pterygium (seen in lichen planus), and leukonychia. Pitting is characterised
by the
presence of small depressions on the nail surface. Ridges or linear elevations
can
develop along the nail occurring in a "lengthwise" or "crosswise" direction.
Beau's lines
are linear depressions that occur "crosswise" (transverse) in the fingernail.
Leukonychia
describes white streaks or spots on the nails. Koilonychia is an abnormal
shape of the
fingernail where the nail has raised ridges and is thin and concave
Koilonychia is often
associated with iron deficiency.
Nail disorders that can be treated with the TNFoc antibody of the invention
alsoinclude psoriatic nails. Psoriatic nails include changes in nails that are
attributable
to psoriasis. In some instances psoriasis may occur only in the nails and
nowhere else
on the body. Psoriatic changes in nails range from mild to severe, generally
reflecting- =
the extent of psoriatic involvement of the nail plate, nail matrix, i.e.,
tissue from which
the nail grows, nail bed, Le., tissue under the nail, and skin at the base of
the nail.
Damage to the nail bed by the pustular type of psoriasis can result in loss of
the nail.
Nail changes in psoriasis fall into general categories that may occur singly
or all
together. In one category of psoriatic nails, the nail plate is deeply pitted,
probably due
to defects in nail growth caused by psoriasis. In another category, the nail
has a yellow
to yellow-pink discoloration, probably due to psoriatic involvement of the
nail bed. A
third. subtype of psoriatic nails is characterized by white areas, which
appear under the
nail plate. The white areas are actually air bubbles marking spots where the
nail plate is
becoming detached from the nail bed. There may also be reddened skin around
the nail.
A fourth category is evidenced by the nail plate crumbling in yellowish
patches, i.e..
onychodystrophy, probably due to psoriatic involvement in the nail matrix. A
fifth
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category is characterized by the loss of the nail in its entirety due to
psoriatic
involvement of the nail matrix and nail bed.
Antbodies obtained using the method of the invention can also be used to treat
nail disorders often associated with lichen planus. Nails in patients with
lichen planus
5 -- often show thinning and surface roughness of the nail plate with
longitudinal ridges or
pterygium.
The antibodies obtained using the invention can be Used to treat nail
disorders,
such as those described herein. Often nail disorders are associated with skin
disorders.
In one embodiment, the invention includes treatment for nail disorders using a
TNFa
10 -- antibody and the methods and compositions of the invention. In another
embodiment,
the nail disorder is associated with another disorder, including a skin
disorder such as
psoriasis. In another embodiment, the disorder associated with a nail disorder
is
arthritis, including psoriatic arthritis.
15 12. Other Skin and Nail Disorders
Antbodies obtained using the method of the invention can be used to treat
other
skirl and nail disorders, such as chronic actinic dermatitis, bullous
pemphigoid, and
alopecia areata. Chronic actinic dermatitis (CAD) is also referred to as
photosensitivity
dermatitis/actinic reticuloid syndrome (PD/AR). CAD is a condition in which
the skin
20 -- becomes inflamed, particularly in areas that have been exposed to
sunlight or artificial
light. Commonly, CAD patients have allergies to certain substances that come
into
contact with their skin, particularly various flowers, woods, perfumes,
sunscreens and
rubber compounds. Bullous pemphigoid refers to a skin disorder characterized
by the
formation of large blisters on the trunk and extremities. Alopecia areata
refers to hair
25 -- loss .characterized by round patches of complete baldness in the scalp
or beard. =
E. 0/her TNFa-Related Disorders
In one embodiment, the invention features a multiple-variable dose method for
treating a TNFa-related disorder in which TNFa activity is detrimental,
comprising
30 -- administering to a patient a TNFa antibody, such that said TNFa-related
disorder is
treated. Examples of TNFa-related disorders in which TNFa activity is
detrimental, are
discussed further below.
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1. Juvenile Arthritis
Tumor necrosis factor has been implicated in the pathophysiology ofjuvenile
arthritis, including juvenile rliewnatoid arthritis (Grom et al. (1996)
Arthritis Rheum.
39:1703; Mangge.et al. (1995) Arthritis Rheum. 8:211). In one embodiment, a
TNFct
antibody is used to treat juvenile rheumatoid arthritis using the methods and
compositions of the invention.
'1 he term "juvenile rheumatoid arthritis" or "JRA." as used herein refers to
a
chronic, inflammatory disease thatoccurs before age 16 that may cause joint or
connective tissue damage. JRA is also referred to as juvenile chronic
polyarthritis and
Still's disease.
JRA causes joint inflammation and stiffness for more than 6 weeks in a child
of
16 years of age or less. Inflammation causes redness, swelling, warmth, and
soreness in
the joints. Any joint can be affected and inflammation may limit the mobility
of
affected joints. One type of JRA can also affect the internal organs.
JRA is often classified into three types by the number of joints involved, the
symptoms, and the presence or absence of certain antibodies found by a blood
test.
These classifications help the physician determine how the disease will
progress and
whether the internal organs or skin is affected. The classifications of JRA
include the
following:
a. Pauciarticular IRA, wherein four or fewer joints are affected.
Pauciarticular is the most common form of JRA, and typically affects large
joints, such
as the knees.
b. Polyarticular HRA, wherein five or more joints are affected. The small
joints, such as those in the hands and feet, are most commonly involved, but
the disease
may also affect large joints.
c. Systemic IRA is characterized by joint swelling, fever, a light skin
rash,
and may also affect internal organs such as the heart, liver, spleen, and
lymph nodes.
Systemic JRA is also referred to as it Still's disease. A small percentage of
these
children develop arthritis in many joints and can have severe arthritis that
continues into
=
adulthood.
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2. Endometriosis
Tumor necrosis factor has been implicated in the pathophysiology of
endometriosis, as women with endometriosis have elevated peritoneal levels of
TNF
(Eisermann el al. (1988) Fertil Steril 50:573; Halme (1989)Am J Obstet Gynecol
161:1718; Mori etal. (1991)Am J Reprod Immunol 26:62; .Taketani etal. (1
992)Am J
Obstei Gynecol 167:265; Overton etal. (1996) Hum Reprod 1996; 11:380). In one
erribOdiment, the TNFcc antibody may be used to treat endometriosis. The term
"endometriosis" as used herein refers to a condition in which the tissue that
normally
lines the uterus (endometrium) grows in other areas of the body, causing pain,
irregular
bleeding, and frequently infertility.
3. Prosiaiitis
Tumor necrosis factor has been implicated in the pathophysiology of
prostatitis,
as men with chronic prostatitis and chronic pelvic pain have significantly
higher levels
of TNF and IL-1 in semen compared to controls (Alexander etal. (1998) Urology
52:744; Nadler et al. (2000) J Urol 164:214; Orhan etal. (2001) Int J Urol
8:495)
Furthermore, in a rat model of prostatitis TNF levels were also increased in
comparison
to controls (Asalcawa et al. (2001) Hinyoldka Klyo 47:459; Harris et al.
(2000) Prostate
44:25). In one embodiment, the TNFa antibody of the invention is used to treat
prostatitis.
The term "prostatitis" as used herein 'refers to an inflammation of the
prostate.
Prostatitis is also referred to as pelvic pain syndrome. Prostatitis manifests
itself in a
variety of forms, including nonbacterial prostatitis, acute prostatitis,
bacterial prostatitis,
and acute prostatitis. Acute prostatitis refers to an inflammation of the
prostate gland
that develops suddenly. Acute prostatitis is usually caused by a bacterial
infection of the
prostate gland. Chronic prostatitis is an inflammation of the prostate gland
that develops
gradually, continues for a prolonged period, and typically has subtle
symptoms. Chronic
prostatitis is also usually caused by a bacterial infection
4. Choroidal neovascularization
Tumor necrosis factor has been implicated in the pathophysiology of chciroidal
neovascularization. For example, in surgically excised choroidal neovascular
membranes, neovascular vessels stained positive for both TNF and IL-1 (Oh H
etal.
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(1999) Invest Ophthalmol Vis Sci 40:1891). In one embodiment, the TNFa
antibody is
used to treat choroidal neovascularization. The term "choroidal
neovascularization" as
used herein refers to the growth of new blood vessels that originate from the
choroid
through a break in the Bruch membrane into the sub¨retinal pigment epithelium
(sub-
RPE) or subretinal space. Choroidal neovascularization (CNV) is a major cause
of
visual loss in patients with the condition.
5. Sciatica
Tumor necrosis factor has been implicated in the pathophysiology of sciatica
(Ozaktay et al. (2002) Eur Spine J. 11:467; Brisby et al.(2002) Eur Spine J.
11:62). In
one embodiment, the TNFa antibody of the invention is used to treat sciatica.
The term
"sciatica" as used herein refers to a condition involving impaired movement
and/or
sensation in the leg, caused by damage to the sciatic nerve. Sciatica is also
commonly
referred to as neuropathy of the sciatic nerve and sciatic nerve dysfunction.
Sciatica is a
form of peripheral neuropathy. It occurs when there is damage to the sciatic
nerve,
located in the back of the leg. The sciatic nerve controls the muscles of the
back of the
knee and lower leg and provides sensation to the back of the thigh, part of
the lower leg
and the sole of the foot. Sciatica can be indicative of another disorder,
including a
lumbar herniated disc, spinal stenosis, degenerative disc disease, isthrnic
spondyloisthesis and piniformis syndrome.
6. Sjogren's syndrome
Tumor necrosis factor has been implicated in the pathophysiology of Sjogren's
syndrome (Koski etal. (2001) Clin Exp Rheztmatol. 19:131). In one embodiment,
the
TNFa antibody of the invention is used to treat Sjogren's syndrome. The term
"Sjogren's' syndrome" asused hereiwreferi to a systemiC inflammatory disorder
characterized by dry mouth, decreased tearing, and other dry mucous membranes,
and is
often associated with autoimmune rheumatic disorders, such as rheumatoid
arthritis.
Dryness of the eyes and mouth are the most common symptoms of this syndrome.
The
symptoms may occur alone, or with symptoms associated with rheumatoid
arthritis or
other connective tissue diseases. There may be an associated enlargement of
the
salivary glands. Other organs may become affected. The syndrome may be
associated
CA 02950817 2016-12-07
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with rheumatoid arthritis, systemic lupus erythematosus, scleroderma,
polymyositis, and
other diseases.
7. Uveitis
Tumor necrosis factor has been implicated in the pathophysiology of uveitis
(Wakefield and Lloyd (1992) Cytokine 4:1; Woon et /2/. (1998) Curr Eye Res.
17:955).
In one embodiment, the TNFa antibody of the invention is used to treat
uveitis. The
terin "uveitis" as used herein refers to an inflammation of the the uvea,
which is the
layer between the sclera and the retina, which includes the iris, ciliary
body, and the
.choroid. Uveitis is also commonly referred to as iritis, pars planitis,
chroiditis,
chorioretinitis, anterior uveitis, and posterior uveitis. The most common form
of uveitis
is anterior uveitis, which involves inflammation in the front part of the eye,
which is
usually isolated to the iris. This condition is often called iritis. In one
embodiment, the
term uveitis refers to an inflammation of the the uvea which excludes
inflammation
associated with an autoimmune disease, Le., excludes autoimmune uveitis.
8. Wet macular degeneration
Tumor necrosis factor has been implicated in the pathophysiology of wet
macular degeneration. In one embodiment, the TNFa antibody of the invention is
used
to treat wet macular degeneration. The term "wet macular degeneration" as used
herein
refers to a disorder that affects the macula (the central part of the retina
of the eye) and
causes decreased visual acuity and possible loss of central vision. Patients
with wet
macular degeneration develop new blood vessels under the retina, which causes
hemorrhage, swelling, and scar tissue.
9. Osteoporosis
Tumor necrosis factor has been implicated in the pathophysiology of
osteoporosis, (Tsutsumimoto et al. (1999) J Bone Miner Res. 14:1751).
Osteoporosis is
used to refer to a disorder characterized by the progressive loss of bone
density and
thinning of bone tissue. Osteoporosis occurs when the body fails to form
enough new
bone, or when too much old bone is reabsorbed by the body, or both. The TNFx
antibody, or antigen-binding fragment thereof, of the invention can be used to
treat
osteoporosis.
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10. Osteoarthrilis
Tumor necrosis factor has been implicated in the pathophysiology of
osteoarthritis, (Venn et al. (1993) Arthritis Rheum. 36:819; Westacott et al.
(1994)J
Rheumatol. 21:17W). Osteoarthritis (OA) is also referred to as hypertrophic
osteoarthritis, osteoarthrosis, and degenerative joint disease. OA is a
chronic
degenerative disease of skeletal joint's, which affects specific joints,
commonly knees,
hips., hand joints and spine, in adults of all ages. OA is characterized by a
number of the
following. manifestations including deieneration and thinning of the articular
Cartilage
with associated development cif "ulcers" or craters, osteophyte formation,
hypertrophy of
bone at the margins, and changes in the synovial membrane and enlargement of
affected
joints. Furthermore, osteoarthritis is accompanied by pain and stiffness,
particularly after
prolonged activity. The antibody, or antigen-binding fragment thereof, of the
invention
can be used to treat osteoarthritis. Characteristic radiographic features of
osteoarthritis
include joint space narrowing, subchondral sclerosis, osteophytosis,
subchondral cyst
formation, loose osseous body (or "joint mouse").
= Medications used to treat osteoarthritis include a variety of
nonsteroidal, anti-
inflammatory drugs (NSAIDs). In addition, COX 2 inhibitors, including
Celebrex,
Vioxx, and Bextra, aand EtoriCoxib, are also used to treat OA. Steroids, which
are
injected directly into the joint, may also be used to reduce inflammation and
pain. In
one embodiment of the invention, TNFcx antibodies of the invention are
administered in
Combination with a NSAIDs, a COX2 inhibitor, and/or steroids.
11. Other
The methods of the invention also can be used to treat various other disorders
in
which TNFcc. activity is detrimental. Examples of other diseases and disorders
in which
TNFcc activity has been implicated in the othophysiology, and thus which can
be
treated using an antibody, or antibody portion, of the invention, include
inflammatory
bone disorders, bone resorption disease, coagulation disturbances, burns,
reperfusion
injury, keloid formation, scar tissue formation, pyrexia, periodontal disease,
obesity,
radiation toxicity, age-related cachexia, Alzheimer's disease, brain edema,
inflammatory
brain injury, cancer, chronic fatigue syndrome, dermatomyositis, drug
reactions, such as
Stevens-Johnson syndrome and Jarisch-fierxheimer reaction, edema in and/or
around
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the spinal cord, familial periodic fevers, Felty's syndrome, fibrosis,
glomerulonephritides
(e.g. post-streptococcal glomerulonephritis or IgA nephropathy), loosening of
prostheses, microscopic polyangiitis, mixed connective tissue disorder,
multiple
myeloma, cancer and cachexia, multiple organ disorder, myelo dysplastic
syndrome,
orchitism osteolysis, pancreatitis, including acute, chronic, and pancreatic
abscess,
polymyositis, progressive renal failure, pseudogout, pyoderma gangrenosum,
relapsing
polychondritis, rheumatic heart disease, sarcoidosis, sclerosing cholangitis,
stroke,
thoracoabdominal aortic aneurysm repair (TAAA), INF receptor associated
periodic
syndrome (TRAPS), symptoms related to Yellow Fever vaccination, inflammatory
diseases associated with the ear, chronic ear inflammation, chronic otitis
media with or
without cholesteatoma, pediatric ear inflammation, myotosis, ovarian cancer,
colorectal
cancer, therapy associated with induced inflammatory syndrome (e.g., syndromes
following IL-2 administration), and a disorder associated with a reperfussion
injury.
The methods of the invention also can be used to treat the following diseases:
Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related
Diseases, acquired pernicious anaemia, acute coronary syndromes, acute and
chronic
pan (different forms of pain), acute Idiopathic Polyneuritis, acute immune
disease
associated with organ transplantation, acute or chronic immune disease
associated with
organ transplantation, acute Inflammatory Demyelinating
Polyradiculoneuropathy, acute
ischemia, acute liver disease, acute rheumatic fever, acute transverse
myelitis, Addison's
disease, adult (acute) respiratory distress syndrome, adult Still's Disease,
alcoholic
cirrhosis, alcohol-induced liver injury, allergic diseases, allergy, alopecia,
Alopecia
areata, Alzheimer's disease, Anaphylaxis, ankylosing spondylitis, ankylosing
spondylitis
associated lung disease, anti-Phospholipid Antibody Syndrome, aplastic anemia,
-
Arteriosclerosis, arthropathy, asthma, atheromalous disease/arteriosclerosis,
atherosclerosis, atopic allergy, Atopic eczema, Atopic dermatitis, atrophic
autoimmune
hypothyroidism, autoimmune bullous disease, Autoimmune dermatitis, autoimmune
diabetes; Autoimmune disorder associatcd with Streptococcus infection,
Autoimmune
Enteropathy, autoimmune haemolytic anaemia, autoimmune hepatitis, Autoimmune
hearing loss, Autoirrunune Lyrnphoproliferative Syndrome (ALPS), autoimmune
mediated hypoglycaemia, autoimmune myocarditis, autoimmune neutropenia,
autoimmune premature ovarian failure, autoinunune thrombocytopenia (AM),
autoimmune thyroid disease, autoimmune uveitis, bronchiolitis obliterans,
Behcet's
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=
disease, Blepharitis, Bronchiectasis, Bullous pemphigoid, cachexia,
Cardiovascular
Disease, Catastrophic Antiphospholipid Syndrome, Celiac Disease, Cervical
Spondylosis, Chiamydia, choleosatatis, chronic active hepatitis, chronic
eosinophilic
pneumonia, chronic fatigue syndrome, chronic immune disease associated with
organ
transplantalion, Chronic isChemia, chronic liver diseases,-ChrOn. IC
inucoeutaneous-
carididiasis, Cicatricial pernPhigoid, Clinically- isolated Syndrome (CIS)
with Risk for
Multiple Sclerosis, common varied immunodeficiency (common variable
hypogammaglobulinaemia), connective tissue disease associated interstitial
lung disease,
Conjunctivitis, Coombs positive haemolytic anaemia, Childhood Onset
Psychiatric
Disorder, Chronic obstructive pulmonary disease (COPD), Crohn's disease,
cryptogenic
autoimmune hepatitis, cryptogenic fibrosing alveolitis, Dacryocystitis,
depression,
dermatitis scleroderma, dermatomyositis, dermatomyositis/polymyositis
associated lung
disease, Diabetic retinopathy, Diabetes mellitus, dilated cardiomyopathy,
discoid lupus
erythematosus, disk herniation, disk protaps, disseminated intravascular
coagulation,
Drug-Induced hepatitis, drug-induced interstitial lung disease, Drug induced
immune
hemolytic anemia, Endocarditis, Endometriosis, endophthalmitis, enteropathic
synovitis,
Episcleritis, Erythema multiforme, erythema multiforrne major, female
infertility,
fibrosis; fibrotic lung 'dfsease, Gestational pemphigoid, giant cell arteritis
(GCA),
glomerulonejihritides, goitrous autoimmune hypothyroidism (Hashimoto's
disease), =
Goodpasture's syndrome, gouty arthritis, graft versus host disease (GVHD),
Grave's
disease, group 13 streptococci (GBS) infection; Guillain-Barre Syndrome (GBS),
haemosiderosis associated lung disease, Hay Fever, heart failure, hemolytic
anemia,
HenoCh-Schoenlein purpurea, Hepatitis B, Hepatitis C, Hughes Syndrome,
Huntington's
chorea, hyperthyroidism, hypoparathyroidism, idiopathic leucopaenia,
idiopathic,
thrornbocytopaenia, Idiopathic Parkinson's Disease, idiopathic interstitial
pneumonia,
idiosyncratic liver disease, IgE-mediated Allergy, Immune hemolytic anemia,
Inclusion
Body Myositis, infectious diseases, Infectious ocular inflammatory disease,
inflammatory bowel disease, Inflammatory demyelinating disease, Inflammatory
heart
disease, Inflammatory kidney disease, insulin dependent diabetes mellitus,
interstitial
pneumonitis, IPFTUIP, Iritis, juvenile chronic arttiritis, juvenile pernicious
anaemia,
Juvenile rheumatoid arthritis, Kawasaki's disease, Keratjtis, Ketatojuntivitis
sicca,
KuSsmaul disease=or Kussmaul-Meier Disease,'Landry's Paralysis, Langerhan's
Cell
Histiocytosis, linear IgA disease, Livedo reticularis, Lyme arthritis,
lymphocytic
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infiltrative lung disease, Macular Degeneration, male infertility idiopathic
or NOS,
malignancies, microscopic vasculitis of the kidneys, Microscopic Polyangiitis,
mixed
connective tissue disease associated lung disease, Morbus Bechterev, Motor
Neuron
Disorders, Mucous membrane pemphigoid, multiple sclerosis (all subtypes:
primary
progressive, secondary progressive, relapsing remitting etc.), Multiple Organ
failure,
myalgic encephalitis/Royal Free disease, Myasthenia Gravis, Myelodysplastic
=
Syndrome, myocardial infarction, Myocarditis, nephrotic syndrome, Nerve Root
Disorders, Neuropathy, Non-alcoholic Steatohepatitis, Non-A.Non-B Hepatitis,
optic
neuritis; organ transplant rejection, ostebarthritiS, OsteolySis, Ovarian
cancer, ovarian
failure, Pancreatitis, Parasitic diseases, Parkinson's disease, Pauciarticular
JRA,
pemphigoid, pemphigus foliaceus, pemphigus vulgaris, peripheral artery
occlusive
disease (PAOD), peripheral vascular disease (PVD), peripheral artery disease
(PAD),
phacogenic uveitis, Phlebitis, Polyarteritis nodosa (or periarteritis nodosa),
Polychondritis, Polymyalgia Rheumatica, Poliosis, Polyartieular JRA,
Polyendocrine
Deficiency Syndrome, Polymyositis, polyglandular deficiency type] and
polyglandular
deficiency type II, polymyalgia rheumatica (PMR), postinfectious interstitial
lung
disease, post-inflammatory interstitial lung disease, Post-Pump Syndrome,
premature
ovarian failure, primary biliary cirrhosis, primary myxoedema, primary
parkinsonism,
primary sclerosing cholangitis, primary sclerosing hepatitis, primary
vasculitis, prostate
and rectal cancer and hematopoietic malignancies (leukemia and lymphoma),
Prostatitis,
psoriasis, psoriasis type 1, psoriasis type 2, lisoriatic arthritis, psoriatic
arthropathy,
pulmonary hypertension secondary to connective tissue disease, pulmonary
manifestation of polyarteritis nodosa, Pure red cell aplasia, Primary Adrenal
= Insufficiency, radiation fibrosis, reactive arthritis, Reiter's disease,
Recurrent
Neuromyelitis Optica, renal disease NOS, Restenosis, rheumatoid arthritis,
rheumatoid
arthritis associated interstitial lung disease, Rheumatic heart disease, SAPHO
(synovitis,
acne, pustulosis, hyperostosis, and osteitis), sarcoidosis, Schizophrenia,
Schmidt's
syndrome, Seleroderma, Secondary Amyloidosis, Shock lung, Scleritis, Sciatica,
Secondary Adrenal Insufficiency, sepsis syndrome, septic arthritis, septic
shock,
seronegative arthopathy, Silicone associated connective tissue disease,
Sjogren's disease
associated lung disease, Sjorgren's syndrome, Sneddon-Wilkinson Dermatosis,
sperm
autoimmunity, spondyloarthropathy, spondilitis ankylosans, Sporadic, Stevens-
Johnson
Syndrome (SJS), Still's disease, stroke, sympathetic ophthalmia, Systemic
inflammatory
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response syndrome, systemic lupus erythematosus, systemic lupus erythematosus
associated lung disease, systemic sclerosis, systemic sclerosis associated
interstitial lung
disease, Takayasu's disease/arteritis, Temporal arteritis, Th2 Type and Thl
Type
mediated diseases, thyroiditis, toxic shock syndrome, toxoplasmic retinitis,
toxic
epidermal necrolysis, Transverse myelitis, TRAPS (Tumor Necrosis Factor
Receptor,
type. B insulin resistance with acanthosis nigricans, Type 1 allergic
reaction, type-1
autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2
autoimmune
hepatitis (anti-LKM antibody hepatitis), Type II Diabetes, ulcerative colitic
arthropathy,
ulcerative colitis, Urticaria, Usual interstitial pneumonia (UIP), uveitis,
vasculitic diffuse
lung disease, Vasculitis, Vernal conjunctivitis, viral retinitis, vitiligo,
Vogt-Koyanagi-
Harada syndrome (VKH syndrome), Wegener's granulomatosis, Wet macular
degeneration, Wound healing, yersinia and salmonella associated arthropathy.
Other examples of disorders that can be used in the methods and compositions
of
the invention are found in US Publication No: 2004-0126372:
- It is understood that all of the above-mentioned TNFa-related disorders
include
both the adult and juvenile forms of the disease where appropriate. It is also
understood
that all of the above-mentioned disorders include both chronic and acute forms
of the
disease. In addition, the multiple-variable dose methods of the invention can
be used to
treat each of the above-mentioned TNFa-related disorders alone or in
combination with
one. another, e.g., a patient who is suffering from uveitis and lupus.
The invention also includes an article of manufacture comprising a packaging
material; an automatic injection device, e.g., autoinjector pen, containing a
syringe filled
with a TNFct inhibitor, such as adalimumab; and a label or package insert
contained
within the packaging material indicating that in studies of the TNFa inhibitor
using the
automatic injection device of the invention for the treatment of rheumatoid
arthritis, the
most common adverse events (AEs) were bronchitis, hypersensitivity, arthritic
pain,
cough and rhinitis.
Other ex'amples of'biological agents which may be dministered to a user using
the automatic injection device, e.g., autoinjector pen, of the invention
include, but are
not limited to, antibodies to or antagonists of human cytokines or growth
factors, for
example, TNF, LT, IL-I, IL-2, IL-3, IL-4, 1L-5, IL-6, 1L-7, IL-8, IL-15, IL-
16, IL-18;
IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF; antibodies to cell
surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45,
CA 02950817 2016-12-07
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CD69, C080 (117.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154
(gp39 or CD4OL); Actemra (tocilizurnab) humanized MAb against interleukin-6
(IL-6)
receptor; TNFcc converting enzyme (TACE) inhibitors; IL-1 inhibitors
(Interleukin-l-
converting enzyme inhibitors, IL-IRA etc.); Interleukin 11; IL-18 antagonists
including
IL-18. antibodies or soluble IL-18 receptors, or IL-18 binding proteins; non-
depleting
anti-CD4 inhibitors; antagonisti.of the co:-stiniUlatory pathway aD80 (B7.1)
or CD86
(137.2) including antibodies, soluble receptors or antagonistic ligands;
agents which
interfere with signalling by proinflarnmatory cytokines such as TNFcc or IL-1
(e.g.
IRAK, NIK, 11C.K 'p38 or MAP kinase inhibitors); IL-1I1 converting enzyme
(ICE)
inhibitors; T-cell signalling inhibitors such as kinase inhibitors;
metafloproteinase
inhibilors; angiotensin converting enzyme inhibitors; soluble cytokine
receptors and
derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives
p75TNFRIgG (EnbrelTm and p55TNFRIgG (Lenercept)), sIL-IRI, sIL-IRII, sIL-6R);
antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFb);
Rituximab; IL-1
TRAP; MRA; CTLA4-Ig; IL-I 8 BP; anti-IL-18; anti-IL15; IDEC-CE9.1/SB 210396
(non-depleting primatized anti-CD4 antibody; IDEC/SmithKline; see e.g.,
Arthritis &
Rheumatism (1995) Vol. 38 S185); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion
proteins; Seragen; see e.g.,.Arthritis & Rheumatism (1993) Vol. 36 1223); Anti-
Tac
(humanized anti-IL-2Ra; Protein Design Labs/Roche); IL-4 (anti-inflammatory
cytokine; DNAX/Schering); IL-10 (SCH 52000; recombinant IL-10, anti-
inflammatory
cytokine; DNAX/Schering); IL-10 and/or IL-4 agonists (e.g., agonist
antibodies); IL-
IRA (IL-1 'receptor antagonist; Synergen/Amgen); anakinra (Kinerete/Amgen);
TNF-
bpis-TNF (soluble TNF binding protein; see e.g., Arthritis & Rheumatism (1996)
Vol.
39 No. 9 (supplement), S284; Amer. J. Physiol. - Heart and Circulatory
Physiology
(1995) Vol. 268, pp. 37-42); R973401 (phosphodiesterase Type IV inhibitor; see
e.g.,
Arthritis & Rheumatism (1996) Vol. 39, No. 9 (supplement), S282); MK-966 (COX-
2
Inhibitor; see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9
(supplement), S81);
Iloprost (see e.g., Arthritis & Rheumatism (1996) Vol. 19_, No. 9
(supplement), S82);
zap-70 and/or Ick inhibitor (inhibitor of the tyrosine kinase zap-70 or lck);
VEGF
inhibitor and/or VEGF-R inhibitor (inhibitors of vascular endothelial cell
growth factor
or Vascular endothelial cell growth factor receptor; inhibitors of
angiogenesis); TNF-
cOnvertase inhibitors; anti-IL-12 antibodies; antiLliq 8 antibodies;
interleukin-11 (see
e.g., Arthritis & Rheumatism(1996) 'Vol. 39, No. 9 (suppleinent), S296);
interleukin-13
CA 02950817 2016-12-07
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(see e.g., Arthritis & Rheumatism (1996) Vol_ 39 No. 9 (supplement), S308);
interleulcin
-17 inhibitors (see e.g., Arthritis & Rheumatism (1996) Vol. 39, No. 9
(supplement),
S120); anti-thymocyte globulin; anti-CD4 antibodies; CD5-toxins; ICAM-I
antisense
phosphorothioate oligo-deoxynucleotides (ISIS 2302; Isis Pharmaceuticals,
Inc.);
soluble complement receptor 1 (TP10; T Cell Sciences, Inc.), efalizumab, and
anti-IL2R
antibodies, including anti-IL 12 antibody (ABT 874); anti-IL 1 8.antibody (ABT
325);
small molecule inhibitor of LCK; small molecule inhibitor of COT; anti-IL1
antibody;
small molecule inhibitor of MK2; anti-CD19 antibody; small molecule inhibitor
of
C)CR3; small molecule inhibitor of CCR5; small molecule inhibitor of gout anti-
E/L
selectin antibody; small molecule inhibitor of P2X7; small molecule inhibitor
of IRAK-
4; small molecule agonist of glucocorticoid receptor; anti-05a receptor
antibody; small
molecule inhibitor of C5a receptor; anti-CD32 antibody; and CD32 as a
therapeutic
protein.
- Other examples of biological agents which may be administered to a
user using
the automatic injection device, e.g., autoinjector pen, of the application
include, but are
not limited to, small molecule inhibitor of ICDR (ABT-I23), small molecule
inhibitor of
Tie-2; methotrexate; prednisone; celecoxib; folic acid; hydroxychloroquine
sulfate;
rofecoxib; etanercept; infliximab; anakinra (Kineree/Arngen); leflunomide;
naproxen;
valdecoxib; sulfasalazine; ibuprofen; methylprednisolone; meloxicam; .
methylprednisolone acetate; gold sodium thiomalate; aspirin; azathioprine;
triamcinolone acetonide; propxyphene napsylate/apap; folate; naburnetone;
diclofenac;
piroxicam; etodolac; diclofenac sodium; oxaprozin; oxycodone hcl; hydrocodone
. bitartrate/apap; diclofenac sodium/misoprostol; fentanyl; anakinra, human
recombinant;
trarnadol hcl; salsalate; sulindac; cyanoeobalamin/fa/ pyridoxine;
acetaminophen;
alendronate sodium; prednisolone; morphine sulfate; lidocaine hydrochloride;
indomethacin; glucosamine sulfate/chondroitin; cyclosporine; sulfadiazine;
amitriptyline
hcl; oxycodone hcl/acetaminophen; olopatadine hcl; misoprostol; naproxen
sodium;
omeprazole; mycophenolate mofetil; cyclophosphamide; rituximab; IL-1 TRAP;
MRA;
CTLA4-IG; IL-I8 BP; ABT-874; ABT-325 (anti-IL 18); anti-IL 15; BIRB-796; SCIO-
469; VX-702; AMG-548; VX-740; Roflumilast; IC-485; CDC-801; and mesopram,
antibiotics, including clarithromycin (Biaxine), ciprofloxacin (Ciproe), and
metronidazole (Flagyle), mesalamine, prednisone, azathioprine, mercaptopurine,
infliximab, budesonide, sulfasalazine, methylprednisolone sod succ,
diphenoxylate/atrop
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sulf, loperarnide hydrochloride, methotrexate, omeprazole, folate,
ciprofloxacin/
dextrose-water, hydrocodone bitartrate/apap, tetracycline hydrochloride,
fluocinonide,
metronidazole, thimerosal/boric acid, hyoscyamine sulfate,
cholestyramine/sucrose,
ciprofloxacin hydrochloride, meperidine hydrochloride, midazolam
hydrochloride,
oxycodone hcl/acetaminophen, promethazine hydrochloride, sodium phosphate,
sulfamethoxazoleitrimethoprim, celecoxib, polycarbophil, propoxyphene
napsylate,
hydrocortisone, multivitamins, balsalazide disodium, codeine phosphate/apap,
colesevelam he!, cyanocobalamin, folic acid, levofloxacin, natal izumab,
methylprednisolone, interferon-gamma, sargramostim (GM-CSF), nonsteroidal,
anti-
inflammatory drugs (NSAlDs), COX 2 inhibitors, including Celebrex , Vioxx ,
and
Bextra , etoricoxib, ibuprofen, diclofenac and misoprostol, naproxen,
meloxicam,
indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, prednisone,
methotrexate,
azathioprine, minocyclin, prednisone, etanercept, and infliximab; rofecoxib;
celecoxib;
folic acid; sulfasalazine; naproxen; leflunomide;.methylprednisolone acetate;
indomethacin; hydroxychloroquine sulfate; sulindac; prednisone; betarnethasone
diprop
augmented; infliximab; methotrexate; folate; triarncinolone acetonide;
diclofenac;
dimethylsulfoxide; piroxicam; diclofenac sodium; ketoprofen; meloxicam;
prednisone;
methylprednisolone; nabumetone; tolmetin sodium; calcipotriene; cyclosporine;
diclofenac; sodium/misoprostol; fluocinonide; glucosamine sulfate; gold sodium
thiomalate; hydrocodone; bitartrate/apap; ibuprofen; risedronate sodium;
sulfadiazine;
thioguanine; valdecoxib; alefacept; RAPTIVA (efalizumab), small molecule
inhibitor
of KDR (ABT-123), small molecule inhibitor of Tie-2, calcipotriene, clobetasol
propionate, triamcinolone acetonide, halobetasol propionate, tazarotene,
methotrexate,
fluocinonide, betarnethasone diprop augmented, fluocinolone, acetonide,
acitretin, tar
shampoo, betamethasone valerate, mometasone furoate, ketoconazole,
pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,
betamethasone,
clobetasol propionate/emoll, fluticasone propionate, azithromycin,
hydrocortisone,
Moisturizing formula, folic acid, desonide; coal tar, difloraione diacetate,
etanercept,
folate, lactic acid, methoxsalen, he/bismuth stibgal/znox/resor,
methylprednisolone
acetate, prednisone, sunscreen, salicylic acid, halcinonide, anthralin,
clocortolone
pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic
acid/sulfur,
desoximetasone, diazepam, emollient, pimecrolimus emollient,
fluocinonide/emollient,
mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl
.myristate,
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psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,
alefacept,
RAPTIVA0 (efalizumab), tacrolimus, pimecrolimus, PUVA, and sulfasalazine.
This invention is further illustrated by the following examples, which should
nut
be construed as limiting.
The following examples describe studies using an exemplary automatic injection
device, e.g., autoinjector or autoinjection pen, of the invention. The
exemplary
autoinjector pen described in the following examples contains a human TNFa
antibody,
e.g., adalimumab (HUMIRAO) and is often referred to as the "HUMIRAOD pen"
below.
Example 1: Use of automatic injection device for administering TNFa inhibitor
Overview / summary ofstudy
Adalimumab is a therapeutic monoclonal antibody for subcutaneous
administration by 2 bioequivalent, single-use injection devices: a ready-to-
use, prefilled
syringe and an integrated, disposable delivery system, the autoinjection pen.
Although
pens have been shown to be preferred over syringes by patients requiring long-
term
subcutaneous administration of medications, there are no data on preference
and pain in
the Use of biologics in patients with chronic inflammatory diseases. Thus; the
objective
of the following study (the TOUCH study) was to assess injection-Site Pain,
safety, and
patient preference of 2 delivery systems of adalimUmab.
The objective of the TOUCH study (Trial Of Usability in Clinical settings of
HUM1RA Autoinjector vs. Prefilled Syringe) was to assess which method of
delivery
rheumatoid arthritis patients preferred: the HUM1RA prefilled syringe that
they were
already using, or the new HUMIRA Pen.
Briefly, patients with rheumatoid arthritis (RA) were enrolled in a Phase II,
multicenter, open-label, single-arm, sequential trial. Patients self-
administered a
standard dose of adalimumab subcutaneously every other week at each of 3
monitored
clinical visits: Visit I (syringe), Visits 2 and 3 (pen). At each visit,
patients rated their
pain at 2 time points and provided their impressions of and preferences for
each delivery
system. Safety was evaluated throughout the study and 70 days after final
study'dose.
= Overall, fifty-two patients were enrolled in-the trial and completed all
3 visits.
Forty patients (76.9%) reported that the pen was less.Painful than the
syringe, 4 patients
(7.7%) found the syringe to be less painful, and 8 patients (15.4%) had no
preference. At
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Visits 2 and 3, patients had significant mean reductions in injection site
pain
immediately post-injection (-1.4 and ¨1.6, respectively, p<0.01) and 15-30
minutes
post-injection (-0.6 at both time points, p<0.01). ¨90% of patients found the
pen more
convenient and easier to use. Patients had statistically significant
reductions in injection-
pain scores from Visit 1 to Visit 2 and from Visit 1 to Visit 3. The types and
cumulative
frequency of AEs during the 2-wk period after the syringe injection and the 4-
wk period
after the 2 pen injections were comparable. Five patients (9.6%) reported AEs,
including
bronchitis, hypersensitivity, arthritic pain, cough and rhinitis after syringe
injection and
8 (15.4%) after pep injection. There were no AEs. leading to discontinuation.
Thus, both
. =
delivery systems were safe, and no significant differences in adverse events
were
reported for either delivery system. In addition, 46 patients (88.5%)
preferred the pen, 3
(5.8%) preferred the syringe, and 3 (5.8%) had no preference. Overall,
patients evaluated
the pen as easier to use, more convenient, requiring less time to inject, and
safer.
In conclusion, patients experienced less pain self-administering adalimumab
via
the 'pen and preferred it over, the syringe. Further, patients perceived the
pen to be easier
to use and more convenient. No differences in safety events were reported
between the 2
bioequivalent delivery systems.
Detailed study
' The following study was performed to assess which method of delivery
patients
(also referred to herein as users) preferred ¨ either the HUMIRAS (also
referred to as
adalimumab) prefilled syringe (PFS) or the new HUMIRMO pen. The following
study
was also performed to compare the two modes of administration, including the
level of
injection-site pain Of the 2 delivery systdms.
= . The study design included a phase II, multicenter, open-label study, that
included
patients who had prior experience administering adalimumab using the prefilled
syringe.
Patients who were >18 years of age, had RA diagnosed according to the 1987
revised
American College of Rheumatology criteria, and had been self-administering
adalimumab 40 mg subcutaneously every other week via the prefilled syringe for
at least
3 months were eligible to enroll. Major exclusion criteria included patients
with a
history of malignancy; patients who were immunocompromised or had a history of
human immunodeficiency virus, demyelinating diseases, or poorly controlled
chronic
disease; patients with active infections requiring treatment; patients with
active
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tuberculosis or a positive purified protein derivative test within the last 6
months;
patients who received live investigational drugs within 30 days or 5 half-
lives; patients
who were regularly using any medication administered via subcutaneous
injection
except for adalimumab; and women who were pregnant or breastfeeding. Patients
in this
study were allowed to continue prestudy dosages of standard antirheumatic drug
therapies.
Patients (n-52) self-injected with the HUMIRAS prefilled syringe at week 0
followed by injections of the HUMIRA pen at weeks 2 and 4, completing
questionnaires at all 3 time points. Patients rated their injection preference
for several
attributes, including overall preference, ease of use, convenience, time to
complete
injection, perceived safety, and pain.
The study included 3 study visits for patient self-administration of
adalimumab every
other week. Each injection was administered under the supervision of a health
care
professional at each visit. At Visit 1, patients self-administered adalimumab
40 mg
subcutaneously via a prefilled syringe held at a 45-degree tingle to the skin.
At Visit 2,
patients were instructed by study personnel on proper administration of
adalimumab via
the pen and on the pen's features (Figure 25), including the display window 40
for viewing
the drug solution before injection and a yellow band to indicate complete
injection;
the sequential opening of safety caps (safety cap 42 protecting the needle and
plum safety
cap 44 respectively) to prevent accidental misfiring; and the proper
positioning, grasp,
and one-touch activation via the plum activator button 46 of the device. At
visits 2 and 3,
patients self-administered adalimumab via pen held at a 90-degree angle to the
skin. Patients
chose to self-inject in either the thigh or abdomen at Visit 1 and were
monitored to ensure they
used the same body location for injection Visits 2 and 3, keeping each
injection at least 2
inches from the previous injection site.
The pen was used by the patient according to the following protocol: patients
were first familiarized with the pen by watching an instructional video and
reading a 5-
step brochure prior to the pen injection. Patients also used a demonstration
pen to
praetiee using the device prio'r to the petrinjecticin. The steps for using
the HUMIKA10
pen included setting up the pen, wherein the pen was removed from the box and
allowed
to acclimate to room temperature by letting it sit for 15-20 minutes. The
patient then
swabs themselves with an alcohol swab prior to injection. The injection site
was chosen
and prepared. HLTMIRAtID was injected using the pen, such that the patient
pressed the
activation button. Once the "click" was heard, the injection began and lasted
about 10
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seconds. After 10 seconds or when the yellow stopped moving in the window, the
injection was complete.
Baseline demographics for the study included patients who had been using the
HUM1RAOD PFS between 3-32 months, with a mean of 15.4 months. Patients
reported
that sdf-injection with PFS too < 1 minute to 5 minutes, with an average of <
1 minute.
Baseline assessments included duration of adalimiunab trdatment,"dtu-ation of
self-
administration of adalitnumab, usual site of injection, length of time to
inject, and
overall impression of adalimumah administration via a syringe. Injection-site
pain was
rated on an 11-point numeric rating scale ranging from 0 (no pain) to 10 (pain
as bad as
it could be) at 2 time points post-injection: immediately post-injection and
15-30
minutes post-injection (Huskisson Lancet. 1974;304;1127-1131 and Jorgensen et
al.
Annals of Pharmacotherapy. 1996;30:729-732). Following each injection,
patients also
rated their overall impressions of the syringe vs. the pen as "extremely
unfavorable,"
"unfavorable," "neutral," "favorable," or "extremely favorable."
At week 0, patients were asked the following information: the amount of time
they have been on HIIMIRAO, their typical injection site, their typical time
of injection,
and their overall impression of the syringe. The most common injection sites
were the
abdomen (25/52) and the thigh (22/52).
A patient=preferencd survey was administerea=following the last visit or upon
early terthination from 'the study. The surVey'asked patients to rate their
overall
preferences (syringe, pen, or no preference) and the rationales for their
preferences. '
Patient preference (syringe, pen, or no preference) was also rated for each of
the
following categories: ease of use, convenience, time to administer injection,
safety, and
less :pain. Patients were also asked to rate their likelihood of switching to
the pen if
available at the same price ("extremely unlikely," "unlikely," "neutral,"
"likely," or
"extremely likely"), and their likelihood of recommending the pen to another
patient
receiving adalimumab (same ratings as above).
At the first and third injections (weeks 2 and 4), patients were asked to rate
the
immediate pain using the pen (scale of 0-10, wherein 0=no pain and 10=pain as
bad as it
could be), the amount of pain at 15-30 minutes (0-10 scale), their overall
impression,
their injection site, whether they experienced a wet or normal injection,
their adherence
to the instructions of the pen, and any additional coniments.
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At the end of the study, patients were given a final preference questionnaire
to
determine the following attributes: overall preference, as well as reasons;
specific
preference, relating to ease of use, convenience, time of injection, safety,
less pain;
whether The patient would be likely to switch from the PFD to the pen; and
whether the
patient would be likely to recommend the pen to other patients using
adalimumab.
Safety was assessed at baseline (for reference) and throughout the study using
clinical laboratory data and physical examination findings. Patients were
monitored for
treatment-emergent adverse event (AE) reports, whether reported spontaneously
by the
patient or by the investigator. A serious AE was defined according to the
Medical
Dictionary for Regulatory Activities (MedDRA version 9.0) as an AE that was
fatal or
life-threatening; required prolonged inpatient hospitalization; resulted in
persistent or
significant disability, congenital anomaly, birth defect, miscarriage, or
elective abortion;
or required medical/surgical intervention to prevent another serious outcome.
Number
and percentage of study patients with AEs were reported from signed informed
consent
up to 70 days after last study visit (5 times the estimated half-life of
adalimumab).
Assessments of drug safety and tolerability also compared the 2- and 4-week
periods
after administration of the syringe and pen, respectively. Routine hematology,
serum
chemistry and serology, and urinalysis tests were conducted through a
certified clinical
laboratory. Laboratory reference ranges were obtained prior to the initiation
of the study
and reviewed by the investigator for screening purposes.
A sample size of approximately 50 patients was needed to demonstrate
equivalence between the injection-site pain scores following administration of
the
prefilled syringe vs. the pen with 80% statistical power, assuming an
equivalence limit
of 5,-a standard deviation (of the differences) of 1.25, and a 1-sided, Type-
I error rate
of 0.025. Evaluations of preference and injection-site pain covered all
participants who
received 1 injection with a syringe and at least 1 injection with the pen.
Baseline
characteristics, preferences, and other categorical data were summarized using
means
and percentages. An "exact" 95% CI was computed to compare the patients who
either
preferred the pen or had no preference with patients who preferred the
prefilled syringe.
Changes from baseline in injection-site pain were analyzed using paired
student Mest
and calculation of 95% Cls. Safety analyses covered all patients who received
at least I
injection. AE rates using each device were compared using the McNemar's test.
All
statistical tests were performed at the 0.05-level of statistical
significance. The statistical
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analysis was performed using SAS , Release 8.2 (SAS Institute, Inc, Cary,
North
Carolina) with a UNIX Version 11.0 operating system.
Interim study results
Interim study /
An interim study examined statistical and descriptive analysis of information
obtained from 17 patients, 11 had all 3 visits and 6 had 2 visits. The study
also
examined baseline and visit 1 data from another 7 patients.
Overall excellent results suggested that the pen is preferred over the
syringe.
Injection pain was comparable with either the pen or syringe, while post
injection site
pain showed differences, mostly in favor of the pen:
- Most patients reported either no or minimal pain during injection with both
devices.
- The majority reported less post-injection site pain with the pen than the
syringe (Mean
values in a 0-10 scale: 3.6 (syringe); 2.4 (pen 1); 1.9 (pen 2)).
Preference: Practically all patients found superior the pen for all rating
attributes such as
overall preference, less pain, ease of use, convenience or safety. The pen was
preferred
in 63 out of 66 answers (6 preference questions to 11 patients).
All 11 patients considered likely (4) or extremely likely (7) switching to and
recommending the pen to others.
Additional details of interim study 1, included the following:
Pain data: (17 patients pen 1; 11 patients pen 2) is shown below in Table 1.1,
where
injection pain (scale 0-10; mean values) - pen 'always' either same or lower
pain than
syringe
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Table 1.1
Injection pain (scale 0-10; mean
values) - pen 'always' either same or lower
pain than syringe
Syringe 0.8
' pen 1 0.2
pen 2 0.1
Table 1.2 below shows details of study 1 based on a different patient
population
described in Table 1.1 Post-injection site pain (scale 0-10; mean values) - 11
patients
reported similar or less pain with the pen, in 6 patients the pen increased
pain from 1 to
3-5
Injection pain (scale 0-10; mean values)
Syringe 3.6
pen 1 2.4
pen 2 1.9
Preference data (EF: e4trernel v. = fav. : neutral. U: unfav EU: extreme)
unfav)
Pen 1: overall impression was mostly EF (7) or F (6).
Pen 2: was mostly EF (6) or F (4). Patient 904 had EU in pen 2, although had
EF in pen
1, but also had an 'extremely likely' to switch and recommend.
Interim study 2
An interim study (following interim study 1 in time) examined 19 patients with
3
injections. The interim study 1 summary included exclusively preference
results based
on descriptive analyses obtained from 31 patients: 19 had all 3 visits, 5 had
2 visits and 7
had just the first visit.
Overall excellent results confirming that the pen is definitely preferred over
the
syringe. Practically all patients found superior the pen for all rating
attributes such as
overall preference, less pain, ease of use, convenience or safety. The pen was
preferred
in 106 out of 114 answers (6 preference, questions to 19 patients).
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18 out of 19 patients preferred the pen and considered extremely likely or
likely
switching to and recommending the pen to others. One patient preferred the
syringe,
considered unlikely to switch and was neutral regarding recommendation.
Additional details included the following:
Subject Impression of Syringe:
n=3 I
Extremely favorable =2 (6.5%)
Favorable = 8 (26%)
Neutral =li (35%)
Unfavorable = 8 (26%)
Extremely Unfavorable = 2 (6.5%)
Subject Impression After Visit 2 - ist_pen Injection
n=24
Extremely Favorable = 12 (50%)
Favorable = 8 (33.3%)
Neutral = 2 (8.3%)
Unfavorable = 1 (4.2%)
Extremely Unfavorable = 1 (4.2%)
Subject Impression Alter Visit 3 - 2nd pen Injection
n=19
Extiemely Favorable = 11(57.9%)
Favorable = 6 (3.1.6%)
Neutral 1 (5.3%)
Extremely Unfavorable = 1 (53%)
Preference Rating After Visit 3 - 2nd pen Injection
n=19
When-asked overall, based on your experience with the HUMIRAO Syringe and the
pen
which do you prefer? 18 of 19 subjects preferred the pen. One subject
preferred the
Syringe.
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When asked which method of injecting HUMIRA1) was preferred in terms of:
Ease of Use - All 19 subjects preferred the pen
Convenience - 18 subject preferred the pen; 1 subject reported No Preference
Time it took to complete the Injection- 17 of 19 subject preferred the pen; 2
subjects
had No Preference
Safety - 17 of 19 subject preferred the pen; 2 subjects had No Preference
Less Pain - 16 of 19 subject preferred the pen; 1 subject preferred the
Syringe; and 2
subjects has No Preference
When asked "How likely would you be to use the pen if it was available at the
same cost
as the Syringe?" 12 subjects reported "Extremely Likely"; 6 subjects reported
"Likely";
and 1 subject reported "Unlikely"
When asked "'How likely would you be to recommend the pen to another HUMIRAS
user?' 11 users reported "Extremely Likely"; 7 users reported "Likely"; and 1
user
reported "Neutral."
Some comments reported by,users who selected their preference as the pen;
"Easy, and less pain, quicker"
"Safer, faster & easier to administer no fear factor"
"Because I don't like needle I can actually see"
"Easier to hold/administer"
"Less painful quick and easy"
"It does it all for you"
"It takes the hassle of having to tab myself+ control the injection out of the
process.
And id didn't seem to hurt as much."
"There is not as much pain"
"Convenience"
"Pain is less severe and lasts a shorter period"
Some corturkentsjogrted by use 8$ to why they did NOT select the Syringe as
their
preference:
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"Hurts"
"More prep time, physical and mental"
"The syringe takes longer, more steps."
"Harder to use"
"Slower more pain"
"Harder to hold/administer"
"Could feel the sting when it goes in, more painful"
"With the syringe you have to push down until done vs. pen push down once and
watch
yellow tab till it stops"
"To me, the pen is easier, with less chance of error on my part"
"Because the pen is easier to use and not as much pain after:
"Slower injection time - more painful"
"Slow process - stings"
Info from the subject who preferred the Syringe:
Ease of use - preferred the pen; Convenience - preferred pen; Time it took to
complete
injection - pen; Safety - pen; Less Pain -Syringe; How likely to use pen -
Unlikely;
How likely to recommend pen - Neutral
Comments - "I seem to be in better control of the injection needle. The second
injection
felt-more painful than the syringe."
Interim Study 3
In interim study 3, the following answers were given in a survey of 35
patients:
= Which method of injecting HUMIRA would you prefer in terms of the time
it
took to complete the injection? pen (n=29); Syringe (n=2); no preference (n=4)
= Which method of injecting HUMIRA would you prefer in terms of safety?
pen
(n=31); syringe (n=0); no preference (n=4)
Results From Complete Study
Patient Disposition and Baseline Characteristics
=' A total of 52 patients were enrolled in the study and completed all 3 study
visits.
No patients discontinued treatment during the study. Baseline demographics and
baseline survey results are included in Table 1.3. Patients enrolled in the
study were
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treated with adalimumab for a mean treatment duration of 15.4 months and were
self-
administering adalimumab with a syringe for the majority of their treatment
periods
(mean duration of self-administration was 14.9 months). In addition,
approximately 655
of patients were receiving concomitant methotrexate, and 35% were receiving
concomitant steroid therapy. Patients were fairly equally divided as to
whether they
usually injected their adalimumab doses in the abdomen or thigh, whereas a
small
percentage alternated between sites. During the study, 29 patients (55.8%)
selected their
abdomens as their injection site, and 23 patients (44.2%) selected their
thighs as their
injection site.
Table 1.3 Baseline Demo, a hies Cr "cal Characteristics and Surve Res onses
Characteristic Overall Population (N=52)
Mean age inycars(SD) 53.8(12.1)
Mean disease duration of rheumatoid arthritis (SD)
8 (7.5) ___
Gender, n (%)
Female 32 (61.5)
Male 20 (38.5)
Race, n (%)
White 46 (88.5)
Black 6(11.5)
Other 0(0)
RA medications in past 12 months, n (%)
Adalimumab 52(100)
Etanercept 2 (3.8)
lnfliximab 2 (3.8)
Other 1 (1.9
Baseline Survey N=52
Duration of adalimumab treatment (mos)
Mean (SD) 15.4 (9.8)
, Median 12.0
Range 3.0-40.0
Duration of self-injecting adalimumab (mos)
Mean (SD) 14.9 (10.0)
Median 12.0
Range 2.0-40.0
Length of time to inject (min)
Mean (SD) 1.6 (4.1)
Median 0.8
Range 02-30.1
Usual injection site, n (%)
Abdomen 25 (48.1)
Thigh 22 (42.3)
Both abdomen and thigh_
¨RA=rheurnatoid arthritis.
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Injection-Site Pain
-=== .=
Injection-site pain ratings arc included in Table 2. At Visit 1, immediately
following the syringe injection, the mean injection-site pain rating was 3.7.
Mean pain
ratings decreased 37% to 2.3 at Visit 2 and 46% to 2.0 at Visit 3, immediately
following
the pen injection. Mean within group changes in injection-site pain
immediately
following the injection at Visit 2 (pen) and Visit 3 (pen) were statistically
significantly
reduced (P = 0.002 and P <0.001, respectively) from Visit 1 (syringe) (Table
2). Mean
pain rating 15-30 minutes post-injection were 0.8 at Visit 1; 0.2 at Visit 2;
and 0.2 at
Visit 3. Similarly, mean within group changes in injection-site pain 15-30
minutes post-
injection at Visit 2 (pen) and Visit 3 (pen) were statistically significantly
reduced (P=
0.004 and P= 0.001, respectively) from Visit 1 (syringe) (Table 2).
Table Injection-Site Pain
Full Analysis Set .
N=52
Within-Group Change from
Visit Week I
Visit Mean Mean SE 95% Cl P-value
Immediately post-injection
Visit 1 (Week I) (Syringe) 3.7
Visit 2 (Week 3) (pen) 2.3 ¨1.4 4 0.43 ¨2.2, ¨0.5
0.002
Visit 3 (Week 5) (pen) 2.0 ¨1.6 0.44 ¨2.5, ¨0.8
<0.001
15-30 minutes post-injection
Visit 1 (Week 1)(Syringe) 0.8
Visit 2 (Week 3) (pen) 0.2 ¨0.6 0.19 ¨1.0, ¨0.2
0.004
Visit 3 (Week 5) (pen) 0.2 ¨0.6 0.16 ¨0.9,-0.2 0.001
Note: The possible range for the assessment of pain is 0 (no pain) to 10 (pain
as bad as it could
be).
Overall Impressions
At Visit 1, patients were equally divided in rating their overall impressions
of
their first syringe injections. Approximately one-third of the patients rated
their overall
impressions of the syringe injection as "favorable" or "extremely favorable,"
approximately one-third were "neutral," and approximately one-third rated it
as
"unfavorable" or "extremely unfavorable" (Table 3). Following the use of the
pen, more
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than 80% of the patients rated their overall impressions of the pen as
"favorable" or
"extremely favorable" at Visit 2 (86.5%) and Visit 3 (88.5%).
Table 3. Overall Impressions of Adalimumab Prefilled Syringe and Autoinjection
pen
Syringe, n (%) pen, n (%)
Visit 1 Visit 2 Visit 3
Response N=52 N=52 N=52
.
EXtremely favorable = .2(3.8) = = 26 (50.0) 33 (63.5)-
Favorable 15 (28.8) 19 (36.5) 13 (25.0)
Neutral 18 (34.6) 3(58) 3(5.8)
Unfavorable 14 (26.9) 1(1.9) _1_()
Extremely unfavorable 3 (5.8) 31.5.8) 1(3.9)
Patient Preference
. The final patient preference survey that was administered following Visit
3
showed that, overall, 88.5% (95% CI 84.1, 98.8) of patients preferred the pen,
5.8%
(95% CI 1.2, 15.9) preferred the syringe, arid 5.8% had no preference (Figure
26).
Patients were asked to list some of the reasons for their preferences. The
majority of
patients who chose the pen as their preferred delivery system said it was
easier to use
and less painful than the syringe. Other reasons why patients preferred the
pen included
the following: no bruising at injection site; faster administration time; less
preparation
time and fewer steps to follow; better control of the device; less force
required; no need
. _ . . . . . . .
to push syringe to insert needle into Skin; no view of the needle; fewer
concerns with
needle storage and disposal; and no need to draw back on syringe to check for
blood.
Patients who chose the syringe as their preferred delivery system gave the
following
reasons: familiarity with the syringe/no need for change; difficulty removing
pen cap;
better control of the injection needle; and less painful than the pen.
When patients were asked to rate specific reasons for their preferences, more
.
preferred the pen over the syringe for (in order from greatest to lowest
percentage) the
following: ease of use; convenience; overall safety and overall attributes
(same
percentage); less time to complete the injection, and less pain (Figure 2).
More than 94%
of patients said they would be likely or extremely likely to use the pen if it
was available
at the same cost as the syringe (Figure 27). Similarly, more than 94% of
patients said
they would recommend the pen to another patient who uses adalimumab (Figure
27).
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Therapy Compliance
At each visit, patients had their injection techniques assessed by a health
care
professional to help determine the effectiveness of the training procedure.
Overall,
patient preparation and injection techniques were rated at 98-100% compliant
(per visit)
for eaCh component assessed (ie, prepared the injection site with alcohol,
inspected the
drug level and quality, removed the caps in order, prepared the skin plateau,
kept the
skin plateau during the injection, positioned the pen correctly, fired the pen
correctly,
kept constant pressure with no pull back, held the injection until complete,
and observed
the yellow stopper in the window when the injection was complete).
Approximately
90% of patients noted that the instructional devices (video or brochures) used
by the
health care professionals provided adequate training.
Safety Assessments
No new safety signals were observed during this study. Adalimumab was
demonstrated to be generally safe and well-tolerated irrespective of syringe
or pen
delivery. No statistically significant differences were observed between AEs
reported
during syringe use vs. pen use either in terms of overall AEs or by individual
MedDRA
preferred term. A total of.13 patients teported a treatment-emergent AE: 5
while using
the prefilled syringe (9.6%) and 10(19.2%) after 2 pen injections. Two
patients reported
an AE during both syringe and pen use. Most AEs were mild to moderate and
included
bronchitis, hypersensitivity, arthritic pain, cough, and rhinitis. Three
infections and 1
drug hypersensitivity reaction were reported. Two patients had a serious AE
while using
the pen. Of these, a 69-year-old white male with a history of hypertension and
coronary
artery disease leading to triple bypass cardiac surgery required
hospitalization because of
exacerbation of congestive heart failure, a diagnosis first established in
1989. This
patient received the second dose of adalimumab via pen once stabilized and
recovered.
The other patient was a 51-year-old white male who required hospitalization
for the
treatment of pneumonia approximately 71 days after the start of study
treatment. No
other TNF-antagonist events of interest, including malignancies, demyelinating
events
(including multiple sclerosis), or lupus-like reactions, were reported during
this study.
No patients discontinued from the study in response to a treatment-emergent
AE, and no
device failures were reported.
CA 02950817 2016-12-07
122
The final results of the study show that 46 out of 52. patients preferred the
pen
(88.5%), while 5.8 % (n=3) had no preference and 5.8% preferred the PFS (n=3).
In
addition, 40 out of 52 patients thought the pen was less painful (76.9%),
while 15.4%
had no preference..Only.7.7% thought the PFS was less painful. Furthermore,
patient
responses indicated' that the pen was easier to use, as 49 of 52 patients
thought the pen
was easier to use (94.2%). Finally, the pelf was deemed more convenient, as 48
of 52
patients thought the pen was more convenient (92.3%). 61.5% (n=32) of the
patients
said that they would be likely to recommend the pen to another HUMIRA user,
while
32.7% (n-17) said they would be likely to recommend and 5.8% (n=3) were
neutral on
the issue. Additional results from the study are shown below in Tables 4-6.
Table 4: Results from questionnaire regarding "How painful was the HUMIRA
injection you just administered?" (both immediately and )5-30 minutes)
WEEK 1
(SYRINGE) VISIT
VISIT N MEAN MEAN
IMMEDIATELY POST INJECTION
' WEEK 3 (PEN) = 52 317 2.3
WEEK 5 (PEN) 52 3.7 2.0
15-30 MIN POST INJECTION
WEEK 3 (PEN) 52 0.8 0.28'
WEEK 5 (PEN) 52 0.8 0.211
P-value <0.001
"P-value 0.001
P-value 0.002
P-value 0.004
Table 5: Subject impression: overall impression
WEEK 1 WEEK 3 WEEK 5
(SYRINGE) (PEN) (PEN)
(N=52) (N=52) (N=52)
n(%) n(%) n(%)
IMPRESSION
EXTREMELY UNFAVORABLE 3 (5.8) 3(5.8) 1 (1.9)
UNFAVORABLE 14 (26.9) 1(1.9) 2 (3.8)
CA 02950817 2016-12-07
123
NEUTRAL 18 (34.6) 3 (5.8) 3 (5.8)
FAVORABLE 15 (28.8) 19 (36.5) 13 (25.0)
EXTREMELY FAVORABLE 2 (3.8) 26 (50.0) 33 (63.5)
Table 6: Method preferred in different cases
Time it took
to complete
Ease of use Convenience the injection Safety Less
pain
Total n=-52 n (%) n (`)/a) n CVO n (%)
(%)
17-).---n 49 (94.2) 48 (92.3) 43 (82.7) 46 (88.5) 40
(76.9)
Syringe 2 (3.8) 1 (1.9) 3 (5.8) 0 4
(7.7)
No preference 1(1.9) 3(5.8) 6(11.5) 6(11.5) 8
(15:4).
The types and cumulative frequency of adverse events (AEs) during the 2-wk
period after the syringe injection and the 4-wk period after the 2 pen
injections were
comparable. Five patients (9.6%) reported AEs, including bronchitis,
hypersensitivity,
arthritic pain, cough and rhinitis after syringe injection and 8 (15.4%) after
pen injection.
There..were no AEs leading to discontinuation.
Although the pen was designed to offer patients greater convenience, it was
unclear what attributes, such as less pain, wciuld drive patients'
preferences. This study
showed that individual attributes ¨ less injection pain, safety, ease of use,
convenience,
and time to complete the injection ¨ all favored the pen over the syringe. In
this study,
the pen showed a statistically significant advantage regarding injection pain,
which was
reduced by 46% immediately after injection, and by 75% 15-30 minutes post-
injection.
Regarding preference, patients were equally divided on their overall
impressions
of the syringe with respect to 5 prespecified categories (ie, "extremely
favorable,"
"favorable," "neutral," "unfavorable," and "extremely unfavorable"). However,
after
switching to the pen, patients' overall impression ratings shifted
significantly toward
either "favorable" or "extremely favorable." Moreover, after only 2 injections
with the
pen, the majority of patients said they were "likely" or "extremely likely" to
switch to
CA 02950817 2016-12-07
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the pen and to recommend the pen to another patient who was being treated with
adalimumab, highlighting patients' quick acceptance of the pen and its
features.
These results may have important treatment implications for patients who
require
long-term TNF inhibitor or other biologic therapies. Because of the
relationship of
patient preference to adherence to therapy (Schwartzman et al. Arthritis
Research &
Therapy. 2004;6(Suppl 2):S19¨S23), a patient's preference for a specific route
of
administration may be a substantial factor in-a physician's selection of a
biologic
therapy. Moreover, adherence to therapy is believed to be one of the most
important
factors in maintaining the long-term benefits of TNF-antagonist therapy, and,
therefore,
the lack of adherence can severely compromise the effectiveness of treatment
(Schwartzman et at. (2004)).
In sum, the pen was determined by patients to be easier to use than a
prefilled
syringe. In addition, patients found that the pen was more convenient than the
syringe
and was less painful than the prefilled syringe. Patients preferred the
HUMIRAO pen to
the HIJMIRAO PFS across all rating attributes. About 90% of the patients
reported an
overall preference for the pen compared to the prefilled syringe. 8 out of 10
patients
also would recommend the pen to other patients using adalimumab. Finally, 80%
of the
patients rated the pen as less painful than the PFS.
This study indicates that patients believed that the adalimumab pen caused
significantly less pain than the traditional prefilled syringe: In additions,
adalimumab-
experienced RA patients preferred subcutaneous injection of adalimumab with an
autoinjection pen over injection with the prefilled syringe. Patients thought
the pen was
easier to use, more convenient, safer, and required less time to inject. With
regard to the
safety profile, no apparent differences were observed between the 2 delivery
systems.
The overall preference of patients for an autoinjection pen device may lead to
increased
adherence to therapy and, in turn, improved clinical outcomes during long-term
therapy
withself-administered biologic therapies, =
Example 2: Assessment of Relative Bioavailability, Safety, and Tolerability of
Single
Doses ofAdalimumab Administered Via an Autoinjector Pen and a Prefilled
Syringe
Rheumatoid arthritis (RA) is a chronic, debilitating disease that requires
long-
term therapy that is safe and efficacious. Current tools of biologic drug
delivery,
CA 02950817 2016-12-07
125
prettied syringes, are painful and cumbersome. Prefilled, disposable,
autoinjector pens,
like those described in the below .example, allow for more convenient dosing.
The purpose of the following example was to compare the bioavailability,
safety,
and tolerability of adalimumab administered subcutaneously via an autoinjector
pen vs.
a prefilled syringe
Study Design
Adalimumab was administered via the Pen or a prefilled syringe in the abdomen
or thigh to healthy adult volunteers in this Phase I, open-label, parallel
group,
multicenter study. Regimen A included a 40-mg subcutaneous dose of adalimumab
via
autoinjector pen, while Regimen B included a 40-mg subcutaneous dose of
adalimumab
via prefilled syringe.
Blood samples were collected by venipuncture prior to dosing (Hour 0); at
Hours
4, 12,-24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 168, 192, 240, 288,
336, and 360;
and at Weeks 3, 4, 5, 6, 7, and 8 after dosing. Serum concentrations of
adalimumab
were determined using a validated double antigen immunoassay. The assay had a
lower
limit of quantilitation Of 3.125 nWmL in ililitted=serum.
= Main Inclusion Criteria included 18-55 years of age and patients were in
general
good health. Main Exclusion Criteria included pregnancy and a history of
positive PPD
skin test.
Pharmacokinetic analysis included analyzing pharmacokinetic (PK) parameters
that
were
estimated using non-compartmental methods. PK parameters included were:
maximum
observed serum concentration (Cmax); time to Cmax (Tmax); area under serum
concentration-time curve (AUC) from Hour 0-360 (AUCO-360); and AUC from Hour
0-1344 (AUCO-1344)
= Statistical analysis was performed using the following considerations. A
four-
way analysis of covariance (ANCOVA) was performed for Tmax and the logarithms
of
AUC and Cmax with regimen, injection site, study center, and sex as the
factors. Body
weight was the covariate. = To assess bioequivalence of the regimens, a two
one-sided
test procedure was carried out for AUC and Cmax via 90% confidence intervals
for the
ratio of regimen central values. The ratio of regimen central values
corresponds to the
difference of the regimen main effects in the ANCOVA model.
CA 02950817 2016-12-07
126
Safety was evaluated based on assessments of adverse events (AEs), physical
examinations, vital signs, and laboratory tests
A total of 295 male and female healthy volunteers enrolled in the study. Of
these, 146 volunteers received a 40-mg dose of adalimumab via an autoinjector
pen and
149 subjects received a 40-mg dose of adalimumab via a prefilled syringe.
Table 7
contains the summary statistics for demographid parameters
. .
Table 7. riasetine Demographic Variables
=
All Randomized
haracteristics Volunteers (N=295)
Age (years) = 37.5 10.6
Weight (kg) 72.4 1 10.9
Height (cm) 168.9 1 9.8
BMI 25.3 2.7
Male 49
% Caucasian 81
All values are Mean SD, except percentages.
Mean serum adalimumab concentration-time profiles were similar in the two
regimens. The pharmacokinetic profiles of the pen and prefilled syringe were
also
comparable between the two injections sites, thigh and abdomen.
Pharmacokinetic.parameters of adalimumab after administration of each of the
two regimens were similar (Table 8). The Tmax, log-transformed Cmax, AUCO-360,
and AUCO-1344 central values for the Pen were not statistically significantly
different
from those for the prefilled syringe (Table 8).
Table 8. Adalimumab Pharmacokinetie parameters in the Autainjector Pen and the
Prefilled Swinge_
Regimens
Adalimumab via Autoinjector
Pharmacokinetic Pen Adalimumab via prefilled syringe
Parameters (N-146 (1\1147)*
max (hours) 142.3 762 151.4 88.5
Crum( (pg/mL) 4.8 1.5 4.8 1.5
AUCO-360
(pg.hr/mL) 1260 352 1276 1 373
AUCO-1344 2454 1 815 2544 952
CA 02950817 2016-12-07
127
l(pg.hrimL)
N = 146 for AUCO-360 and AUCO-1344.
In both regimens a single 40-mg dose of adalimumab is administered
subcutaneously.
All values are Mean SD.
The 90% confidence intervals for log-transformed AUCO-360, AUCO-1344, and
Cmax were contained within the 0.80 to 1.25 range indicating that the
autoinjector test
Regimen A was bioequivalent to the prefilled syringe reference Regimen B at
both
subcutaneous locations, thigh and abdomen (Table 9)
Table 9. Relative Bioavailability and 90% Confidence Intervals for the
Bioequivalence
Assessment by Injection Site
Central Value* Relative Bioavailabilit
Prefilled 90%
Regimens Pent Syringet Point Confidence
k vs. B PK Parameters (N-146) (N=149) Estimate = Interval
Cniax 4.43 4.38 1.012 0.922-1.111
Abdomen AUCO-360 1166 1138 1.025 0.931-1.129
AUCO-1344 2169 2242 0.968 0.858-1.091
Cmax 4.62 4.89 0.944 0.860-1.037
high AUCO-360 1205 1319 0.914 0.829-1.007
AUCO-1344 . 2332 2547 0.915 0.812-1.033
* Antilogarithm of the least squares means For logarithms,
t Regimen A: 40 mg adalimumab administered subcutaneously via an autoinjector.
Regimen B: 40 mg adalimumab administered subcutaneously via a prefilled
syringe.
Antilogarithm of the difference (Pen minus prefilled syringe) of the least
squares means for
logarithms.
The autoinjector was well-tolerated in this study, with a safety profile
comparable to that of the prefilled syringe (Table 10)
'futile JO. Adverse Events k.2% in the Population
Autoinjector Pen Prefilled Syringe
N=146 N = 149
n (%) n (%)
fly AE 70 (48) 60 (40)
Headache 29 (20) 28 (19)
Upper Respiratory Tract Infection 9 (6) 13 (9)
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128
Nasal Congestion 9 (6) 7 (5)
Pain (Limbs) 2 (1) 7 (5)
Constipation 7(5) 2(1)
No deaths or discontinuations duecto'acl:/erse events occurred during the
study.
One volunteer reported a serious adverse event of appendicitis requiring
surgery and
hospitalization on Study Day 20. The subject requested to continue
participation in the
study following her release from the hospital, and was allowed to continue
following a
complete medical evaluation. The majority of the treatment-emergent adverse
events
were assessed by the investigators as not related or possibly related to the
study drug and
mild in severity.
In conclusion, the autoinjector pen was bioequivalent to the prefilled
syringe.
The two regimens were also bioequivalent at each injection site, abdomen and
thigh.
The safety profile of the pen was comparable to the safety profile of the
prefilled syringe
Example 3: Introduction of a HUMIRA Automatic Injection Device as Compared to
a
Pre-Filled Syringe for Delivery of HUMIRA
= A HUMIRA representative visits a physician who has previously prescribed
HUMIRA PFS to patients. The representative delivers an oral presentation to
the
physician in which the TOUCH study and the results thereof are described for
the
physician (for TOUCH study, see, for example, Example 1 above). In particular,
the
representative conveys to the physician that 90% of patients reported an
overall
preference for the HUMIRA Pen compared to the PFS, 8 out of 10 would
recommend
the Pen to other HUMIRA patients and 80% of patients rated the Pen as less
painful
than the PFS. Additionally, the representative provides to the physician a
flipchart and a
DVD, each of which describe the TOUCH study and convey that 90% of patients
reported an overall preference for the HUMIRA Pen compared to the PFS, 8 out
of 10
would recommend the Pen to other HUMIRA patients and 80% of patients rated
the
Pen as less painful than the PFS.
CA 02950817 2016-12-07
129
Example 4: Methods of Training for Use of a HUMIRA1 Automatic Injection Device
A HUMIRA representative visits a physician who has previously prescribed
HUMIRA PFS to patients. The representative delivers an oral presentation to
the
physician describing how the HUMIRA Pen is used to deliver a dose of HUMIRA
to
a patient. This presentation includes instructions to carry out the following
steps:
(i) remove the HUMIRA Pen from the refrigerator 15 to 20 minutes before
injection;
(ii) choose an injection site on thigh or stomach (wherein the site should be
at
least one inch from a previous injection site and at least two inches from the
navel) and wipe the injection site with an alcohol swab;
(iii) examine the HUMIRA solution in the HUMIRA Pen through a window
in the Pen to make sure that the liquid is clear and colorless. Also, holding
the
Pen such that the needle end is pointing downward, check to make sure that the
level of the liquid is the same as or close to a line visible through the
window (to
ensure the proper dosage is present);
(iv) remove caps from the needle end and activator button end of the Pen.
Gently squeeze a sizeable area of cleaned skin and place the Pen at a 90-
degree
angle flush against the skin. Press the activator button, keeping the Pen
firmly
against the skin, and listen for a "click". Maintain pressure on the activator
button and count to 10 seconds. Ensure that the yellow indicator in the
display
window appears in full view and stops; and
(v) dispose of the Pen in an appropriate container(e.g., a Sharps container).
Additionally, the representative provides to the physician a flipchart and a
DVD that
convey the instructions to carry out steps (1) to (v) as set forth above.
Additionally, the
representative provides to the physician a training kit, wherein the kit
includes (1) a
demonstration automatic injection device, which mimics the HUMIRA Pen but
lacks
the needle and the HUMIRA dose, (2) a brochure that conveys instructions to
carry out
steps (i) to (v) as set forth above and (3) an audiovisual device (VI-IS
cassette or DVD)
that conveys instructions to carry out steps (i) to (v) as set forth above.
CA 02950817 2016-12-07
130
EQUIVALENTS
= Those skilled in the art will recognize, or be able to ascertain using no
more than
routine experimentation, many equivalents to the specific embodiments of the
invention
described herein. Such equivalents are encompassed by the following claims.
CA 02950817 2017-01-18
130a
The sequences in the sequence listing in electronic form are reproduced in
the following table.
SEQUENCE TABLE 11
<110> ABBVIEBIOTECHNOLOGYLTD.
<120> AUTOMATIC INJECTION DEVICE
<130> 36656-2517
<140> CA 2,950,817
<141> 2007-06-29
<160> 37
<170> FastSEQ for Windows Version 4.0
<210> 1
<211> 107
<212> PRT
<213> Artificial Sequence ,
<220>
<223> adalimumab light chain variable region
<400> 1
Asp Ile Gin Met Thr Gin ser Pro Ser Ser Leu Ser Ala Ser val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gin Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gin Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys
100 105
<210> 2
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> adalimumab heavy chain variable region
CA 02950817 2016-12-07
130b
<400> 2
Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu ser cys Ala Ala ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp ASn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
100 105 110
Gin Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> adalimumab light chain variable region CDR3
<220>
<221> VARIANT
<222> 9
<223> xaa = Thr or Ala
<400> 3
Gin Arg Tyr Asn Arg Ala Pro Tyr Xaa
1 5
<210> 4
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> adalimumab heavy chain variable region CDR3
<220>
<221> VARIANT
<222> 12
<223> Xaa = Tyr or Asn
<400> 4
Val ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Xaa
1 5 10
<210> 5
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> adalimumab light chain variable region CDR2
<400> 5
Ala Ala Ser Thr Leu Gin Ser
1 5
<210> 6
<211> 17
<212> PRT
<213> Artificial Sequence
CA 02950817 2016-12-07
130c
<220>
<223> adalimumab heavy chain variable region CoR2
<400> 6
Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp ser Val Glu
1 5 10 15
Gly
<210> 7
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> adalimumab light chain variable region CDR1
<400> 7
Arg Ala Ser Gin Gly Ile Arg Asn Tyr Leu Ala
1 5 10
<210> 8
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> adalimumab heavy chain variable region cDR1
<400> 8
Asp Tyr Ala Met His
1 5
<210> 9
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 2SD4 light chain variable region
<400> 9
Asp Ile Gin met Thr Gin Ser Pro Ser Ser Leu ser Ala Ser Ile Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gin Gly Ile Arg Asn Tyr
20 25 30
Lou Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu LOU Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gin Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gin Lys Tyr Asn Ser Ala Pro Tyr
85 90 95
Ala Phe Gly Gin Gly Thr Lys val Glu Ile Lys
100 105
<210> 10
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 2SD4 heavy chain variable region
<400> 10
Gin val Gin Leu val Glu Ser Gly Gly Gly Lou val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
CA 02950817 2016-12-07
130d
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val
35 40 45
ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp ser Val
50 55 60
Glu Gly Arg he Ala Val Ser Arg Asp Asn Ala Lys Asn Ala Leu Tyr
65 70 75 80
Leu Gin Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Lys Ala ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 11
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 2504 light chain variable region CDR3
<400> 11
Gln Lys Tyr Asn Ser Ala Pro Tyr Ala
1 5
<210> 12
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> EP 612 light chain variable region CDR3
<400> 12
Gln Lys Tyr Asn Arg Ala Pro Tyr Ala
1 5
<210> 13
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL10E4 light chain variable region C0R3
<400> 13
Gln Lys Tyr Gin Arg Ala Pro Tyr Thr
1 5
<210> 14
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL100A9 light chain variable region CDR3
<400> 14
Gin Lys Tyr Ser Ser Ala Pro Tyr Thr
1 5
<210> 15
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VLL10002 light chain variable region CDR3
<400> 15
CA 02950817 2016-12-07
130e
Gln Lys Tyr Asn ser Ala Pro Tyr Thr
1 5
<210> 16
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VLLOF4 light chain variable region CDR3
<400> 16
Gin Lys Tyr Asn Arg Ala Pro Tyr Thr
1 5
<210> 17
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> LoE5 light chain variable region CDR3
<400> 17
Gln Lys Tyr Asn Ser Ala Pro Tyr Tyr
1 5
<210> 18
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VLLOG7 light chain variable region CDR3
<400> 18
Gin Lys Tyr Asn Ser Ala Pro Tyr Asn
1 5
<210> 19
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VLLOG9 light chain variable region CDR3
<400> 19
Gln Lys Tyr Thr Ser Ala Pro Tyr Thr
1 5
<210> 20
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VLL0111 light chain variable region CDR3
<400> 20
Gin Lys Tyr Asn Arg Ala Pro Tyr Asn
1 5
<210> 21
<211> 9
<212> PRT
<213> Artificial sequence
CA 02950817 2016-12-07
130f
<220>
<223> VLLOH10 light chain variable region CDR3
<400> 21
Gin Lys Tyr Asn Ser Ala Ala Tyr Ser
1 5
<210> 22
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL1B7 light chain variable region CDR3
<400> 22
Gin Gin Tyr Asn Ser Ala Pro Asp Thr
1 5
<210> 23
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> vL1C1 light chain variable region cDR3
<400> 23
Gin Lys Tyr Asn Ser Asp Pro Tyr Thr
1 5
<210> 24
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL0.1F4 light chain variable region CDR3
<400> 24
Gin Lys Tyr Ile Ser Ala Pro Tyr Thr
1 5
<210> 25
<211> 9
<212> PRT =
<213> Artificial Sequence
<220>
<223> VL0.1H8 light chain variable region C0R3
<400> 25
61n Lys Tyr Asn Arg Pro Pro Tyr Thr
1 5
<210> 26
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> LoE7.A light chain variable region CDR3
<400> 26
Gin Arg Tyr Asn Arg Ala Pro Tyr Ala
1 5
<210> 27
<211> 12
<212> PRT
CA 02950817 2016-12-07
130g
<213> Artificial sequence
<220>
<223> 2SD4 heavy chain variable region CDR3
<400> 27
Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Asn
1 5 10
<210> 28
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VH1B11 heavy chain variable region CDR3
<400> 28
Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Lys
1 5 10
<210> 29
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VH108 heavy chain variable region CDR3
<400> 29
Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Tyr
1 5 10
<210> 30
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VH1A11 heavy chain variable region CDR3
<400> 30
Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Asp
1 5 10
<210> 31
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VH1B12 heavy chain variable region CDR3
<400> 31
Ala Ser Tyr Leu Ser Thr Ser Phe Ser Leu Asp Tyr
1 5 10
<210> 32
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> vH1E4 heavy chain variable region CDR3
<400> 32
Ala Ser Tyr Leu Ser Thr Ser Ser Ser Leu His Tyr
1 5 10
CA 02950817 2016-12-07
130h
<210> 33
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VH1F6 heavy chain variable region CDR3
<400> 33
Ala Ser Phe Leu Ser Thr Ser Ser Ser Leu Glu Tyr
1 5 10
<210> 34
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> 3C-H2 heavy chain variable region CDR3
<400> 34
Ala Ser Tyr Leu Ser Thr Ala Ser Ser Leu Glu Tyr
1 5 10
<210> 35
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> VH1-02.N heavy chain variable region CDR3
<400> 35
Val Ser Tyr Leu ser Thr Ala Ser Ser Leu Asp Asn
1 5 10
<210> 36
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> adalimumab light chain variable region
<400> 36
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtagggga cagagtcacc 60
atcacttgtc gggcaagtca gggcatcaga aattacttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaatcagg ggtcccatct 180
cggttcagtg gcagtggatc tgggaCagat ttcactctca ccatcagcag cctacagcct 240
gaagatgttg caacttatta ctgtcaaagg tataaccgtg caccgtatac ttttggccag 300
gggaccaagg tggaaatcaa a 321
<210> 37
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> adalimumab heavy chain variable region
<400> 37
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ccggcaggtc cctgagactc 60
tcctgtgcgg cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggaatg ggtctcagct atcacttgga atagtggtca catagactat 180
gcggactctg tggagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
clgcaaatga acagtctgag agctgaggat acggccgtat attactgtgc gaaagtctcg 300
taccttagca ccgcgtcctc ccttgactat tggggccaag gtaccctggt caccgtctcg 360
agt 363
