Note: Descriptions are shown in the official language in which they were submitted.
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METHOD OF OPTIMIZING A FILLING RECIPE FOR A DRUG CONTAINER
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the filing date of U.S.
Provisional Patent Application No. 63/191,797,
filed May 21, 2021, which is hereby incorporated by reference in its entirety.
FIELD OF DISCLOSURE
[0002] The present disclosure generally relates to filling recipes for drug
containers and, more particularly, to a universal
method of optimizing a filling recipe for a drug container.
BACKGROUND
[0003] Existing filling recipes for filling drug containers, such as
recipes for loading mAb formulation in a nested syringe and
vial line, are known. However, many existing filling recipes create several
problems, including extended fill weight optimization
cycles, substantial rejected units, and a lower manufacturing yield. In
addition, existing filling recipes often have low process
capability demonstrated by a poor process capability index, e.g., Cpk, <1.33
value.
[0004] More specifically, existing fill recipes are individually tailored
to a single drug product, each of which has a unique filling
process and set of operating parameters. As a result, a pump in a
manufacturing facility carrying out the filling recipe must be
calibrated each time a new filling recipe is needed for a new drug product. In
addition, the time involved to calibrate the pump or
related equipment in a manufacturing facility before beginning the filling
process according to a particular filling recipe is often
lengthy. For example, there are typically many cycles needed, such as multiple
number of strokes of the pump, until the pump is
able to operate according to a particular filling recipe. This increases the
overall time to fill a drug container, such as a syringe or
a vial, using a specific filling recipe for a drug product, leading to
inefficiencies in the manufacturing and filling processes. In
addition, existing filling recipes typically migrate out of a desired range of
a fill volume of the container, causing problems in the
manufacturing system and process. In one example, when the fill volume is
outside of the desired fill volume range, the unit is
discarded, and the pump must be retaught how to fill the target within the
range, again leading to inefficiencies in the
manufacturing process.
SUMMARY
[0005] In accordance with a first aspect, a method of filling a vial
comprises providing a pump corresponding to a vial, and
setting a drip retraction parameter for the pump to any value equal to or less
than 20 degrees. The method further comprises
setting a no adjustment limit for a fill weight of the vial to Ti, with Ti
being at or in a range of about 2% more or less than a fill
weight of a target fill weight TO, and wherein a process performance index Cpk
(Cpk) for the vial throughout a fill cycle exceeds a
minimum value.
[0006] In accordance with a second aspect, a method of filling a plurality
of vials of a nested syringe and vial line comprises
providing a plurality of pumps corresponding to a plurality of vials of a
nested syringe and vial line, and setting a drip retraction
parameter for each pump in the plurality of pumps to any value equal to or
less than 20 degrees. The method also includes filling
each vial of the plurality of vials with a drug product via a corresponding
pump of the plurality of pumps; and wherein a Cpk for
each vial of the plurality of vials exceeds a minimum value throughout a fill
cycle.
[0007] In accordance with yet another aspect, a method of optimizing a
filling recipe for a nested syringe and vial line
comprises setting a drip retraction parameter for at least one pump in an
offline manufacturing system corresponding to any
value equal to or less than 20 degrees, and monitoring a performance of the at
least one pump with the drip retraction parameter
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of the at least one pump set to any value equal to or less than 20 degrees.
The method also includes obtaining at least a
minimum value for a Cpk for the at least one container throughout at least one
fill cycle and for at least one drug product using
the at least one pump in the offline manufacturing system; and finalizing a
filling recipe for a nested syringe and vial line using
data from fill cycles of the at least one drug product using the at least one
pump in the offline manufacturing system.
[0008] In accordance with yet another aspect, a method of filling a vial may
comprise providing a pump corresponding to a
vial, setting a drip retraction parameter for the pump to any value equal to
or less than 20 degrees, and setting a no adjustment
limit for a fill weight of the vial to any value within a range of a target
fill weight TO and Ti, with Ti being at or in a range between
the target fill weight TO and T2. So configured, a minimum value for a process
performance index Cpk (Cpk) for the vial
throughout a fill cycle is exceeded.
[0009] In some aspects, setting a drip retraction parameter for the pump to
any value equal to or less than 20 degrees may
comprise setting the drip retraction parameter for the pump to one of 10
degrees, 20 degrees, or any value in a range of 10
degrees to 20 degrees. In addition, the method may further comprise setting an
end drip retraction value to 290 degrees when
setting the drip retraction parameter to 20 degrees or setting an end drip
retraction value to 280 degrees when setting the drip
retraction parameter to 10 degrees. In addition, providing a pump
corresponding to a vial may comprise providing a pump
corresponding to a vial of a nested syringe and vial line.
[0010] In other aspects, providing a pump corresponding to a vial may
comprise providing one or more of a first fill set or a
second fill set, the first fill set including a peristaltic pump filling
assembly having a needle with an outer diameter of about 2.0mm,
and the second fill set including a peristaltic pump filling assembly having a
needle with an outer diameter of about 3.0mm.
[0011] In still other aspects, wherein a Cpk for the vial exceeds a minimum
value throughout a fill cycle may comprise one or
more of: (1) the Cpk for the vial exceeds a value of 1.33; or (2) the Cpk for
the vial exceeds the minimum value during a
temperature range throughout the fill cycle, the temperature range is one of:
(1) 5 (+/-3) degrees Celsius; (2) 20 (+/-5) degrees
Celsius; or (3) 10 to 19 degrees Celsius.
[0012] In other aspects, the method may further comprise filling the vial
with a drug product via the pump, wherein the drug
product has one or more of the following characteristics: (a) a density in a
range of about 1.0-1.2 g/cm3; (b) a viscosity in a range
of about 1.0-10.0 cP; and (c) a surface tension in a range of about 40.0-72.7
mN/m. In one example, the drug product has a
density in a range of 1.0-1.2 g/cm3; a viscosity in a range of about 1.0-10.0
cP; and a surface tension in a range of about 40.0-
72.7 mN/m. In another example, the drug product comprises a biologic drug
(e.g., peptides, mAb, siRNA) or a small molecule
drug.
[0013] In still other aspects, the method may further comprise monitoring a
performance of the filling recipe in the nested
syringe and vial line and obtaining at least a minimum value for the Cpk for
the at least one container for each pump in a plurality
of pumps in the nested syringe and vial line.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] It is believed that the disclosure will be more fully understood
from the following description taken in conjunction with
the accompanying drawings. Some of the drawings may have been simplified by
the omission of selected elements for the
purpose of more clearly showing other elements. Such omissions of elements in
some drawings are not necessarily indicative of
the presence or absence of particular elements in any of the example
embodiments, except as may be explicitly delineated in the
corresponding written description. Also, none of the drawings is necessarily
to scale.
[0015] FIG. 1 is a schematic representation of one embodiment of an offline
filling system utilizing a filling recipe of the present
disclosure;
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[0016] FIG. 2A is a perspective view of a filler of the system of FIG. 1;
[0017] FIG. 2B is a portion of the filler of FIG. 2A;
[0018] FIG. 2C is a perspective view of a fill set of the system of FIG. 1;
[0019] FIG. 2D is a perspective view of another fill set of the system of
FIG. 1;
[0020] FIG. 2E is a perspective view of an exemplary fill target of the
system of FIG. 1;
[0021] FIG. 3A is a chart depicting parameters of each of the fill sets of
FIG. 1;
[0022] FIG. 3B is a chart depicting in process control parameters of the
fill sets of FIG. 1;
[0023] FIG. 3C is a chart depicting product characteristics of drug
products for use with the methods of the present disclosure;
[0024] FIG. 4 is a flow chart depicting a filling recipe parameter
optimization strategy relative to the filling recipe of the present
disclosure;
[0025] FIG. 5A is a perspective view of fill performance results of a vial
after filling at various drip retraction values;
[0026] FIG. 5B is a chart depicting aspects of an exemplary fill recipe
used with the fill performance results of FIG. 5A;
[0027] FIG. 6A depicts an exemplary filling recipe according to one aspect
of the present disclosure;
[0028] FIG. 6B is a graph depicting filling performance results of the
filling recipe of FIG. 6A;
[0029] FIG. 6C is a chart depicting the filling performance results of the
graph of FIG. 6B;
[0030] FIG. 7A is a chart depicting needle parameters of a needle used with
a filling recipe of the present disclosure;
[0031] FIG. 7B is a chart depicting pump parameters of at least one pump
used with a filling recipe of the present disclosure;
[0032] FIG. 8A is a graph depicting filling performance results of the
filling recipe of the present disclosure in a temperature
range of 10¨ 11 degrees Celsius and using a second fill set of the system of
FIG. 1;
[0033] FIG. 8B is a chart depicting the filling performance results of the
graph of FIG. 8A;
[0034] FIG. 9A is a graph depicting the filling performance results of the
filling recipe of the present disclosure at a temperature
of about 19 degrees Celsius and using the second fill set of the system of
FIG. 1;
[0035] FIG. 9B is a chart depicting the filling performance results of the
graph of FIG. 9A;
[0036] FIG. 10A is a graph depicting the filling performance results of the
filling recipe of the present disclosure at a
temperature of about 10-11 degrees Celsius and using the first fill set of the
system of FIG. 1;
[0037] FIG. 10B is a chart depicting the filling performance results of the
graph of FIG. 10A;
[0038] FIG. 11A is a graph depicting the filling performance results of the
filling recipe of the present disclosure at a
temperature of about 19 degrees Celsius and using the first fill set of the
system of FIG. 1;
[0039] FIG. 11B is a chart depicting the filling performance results of the
graph of FIG. 11A;
[0040] FIG. 12 is a schematic representation of a manufacturing line in a
manufacturing plant using the optimized filling recipe
of the present disclosure;
[0041] FIG. 13A is a perspective view of a nested syringe and vial line of
the manufacturing line of FIG. 12;
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[0042] FIG. 13B is a schematic view of the nested syringe and vial line of
FIG. 13A;
[0043] FIG. 13C is a perspective view of a plurality of pumps corresponding
to a plurality of vials of the nested syringe and vial
line of FIGS. 13A-13B;
[0044] FIG. 14 is a chart depicting filling performance results of the
filling recipe of the present disclosure in at least one of the
nested syringe and vial line of FIG. 12; and
[0045] FIG. 15 is a chart depicting filling performance results of a
previously used filling recipe used in a nested syringe and
vial line.
DETAILED DESCRIPTION
[0046] Generally, an efficient filling recipe for filling formulations
comprising therapeutic proteins in a nested syringe and vial
line is disclosed. The universal filling recipe include a drip retraction
parameter optimization within a specified value, which
results in a significantly more efficient fill recipe compared to other
existing, known filling recipes. In particular, and for example,
the new filling recipe of the present disclosure may be used with many
different drug products and results in 95% reduction in fill
weight optimization cycles. This led to an improvement of 10-30% increase
utilization of a nested syringe and vial line fill time
and potentially saving a significant number of units, such as vials, from
rejection. In at least one example, the drug products
referred to herein comprise therapeutic proteins, such as monoclonal
antibodies, as explained more below.
[0047] More specifically, and referring now to FIG. 1, an offline
manufacturing system 10 utilizing a filling recipe of the present
disclosure is depicted. In one example, the offline manufacturing system 10 is
a small scale bench set-up in a pilot facility, which
made various tests related to the new filling recipe easier to assess and
update based on test results for various attempted
recipes, for example. The offline manufacturing system 10 includes a filler
12, a first fill set 14, and a second fill set 16. The first
fill set 14 includes a corresponding first fill target 18, such as a vial, and
the second fill set 16 likewise includes a corresponding
second fill target 20, also such as a vial. In one example, the filler 12 is a
Bausch+Strobel (B&S) scale-down filler in which recipe
optimization, including many experiments, were conducted before arriving at
the optimal, universal filling recipe of the present
disclosure. While the specific B&S scale-down filler was used, it will be
appreciated that various other fillers may also or
alternatively be used. In addition, while each of the first and second fill
targets 18, 20 are referred to as a vial in one example, it
will be understood that the fill targets 18, 20 may alternatively and more
generally be any other similar drug container and still fall
within the scope of the present disclosure. As explained more below, the
optimal filling recipe selected from the recipe
optimization from the scale-down filler 12 and first and second fill sets 12,
16 is transferable to a manufacturing line, such as a
nested syringe and vial line in FIGS. 13A and 13B.
[0048] Referring now to FIGS. 2A-2E, a perspective view of each of the
filler 12, first and second fill sets 14, 16 and first and
second fill targets 18, 20 of FIG. 1 is depicted. In FIG. 2A, the filler 12 is
a Bausch+Strobel Filler, a bench scale down filler, and
more generally a developmental filler to support clinical and commercial
manufacturing, as explained more below. Exemplary
containers that may be used with this filler include bulk ISO 2R, 6R, 20R,
3cc, 5cc, 10cc, 20cc vials, bulk 1mL glass and 1 mL
plastic syringes, and bulk 5cc plastic cartridges. The filler 12 includes a
dosing vessel 21, a pump 22, such as a peristaltic
pump, and a product bag 23. FIG. 2B depicts a portion of the filler 12 of FIG.
2A. In particular, the pump 22 is depicted
cooperating with a fill target, such as the first fill target 18 or the second
fill target 20. In this example, the first and second fill
targets 18, 20 are the same vial, but may also be any other container and
still fall within the scope of the present disclosure.
[0049] Referring now to FIG. 2C, the first filling set 14 of FIG. 1 is
depicted. The first filling set 14 is a peristaltic pump and
includes a bag 27, tubing 28A, and a needle 29A. The tubing 28A is coupled to
the bag 27 at one end and the fill target 18 at the
other end, such that the fluid in the bag is able to be drawn into the tubing
and to the fill target 18 by way of the needle 29A, for
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example. In this example, the outer diameter of the needle 29A is 2.0m, the
inner diameter of the needle is 1.6mm, and the inner
diameter of the pump tubing 28A is 1.6 mm. In addition, the tubing 28A
branches into two tubing and converges again. The two
tubing have the same inner diameter in this example. For example, the inner
diameter of the tubing 28B is 1.6mm. In a similar
manner, FIG. 2D depicts the second fill set 16 of FIG. 1. Like the first fill
set 14, the second fill set 16 is a peristaltic pump and
includes the bag 27, tubing 28B, and a needle 29B, which is different from the
needle 29A of the first fill set 14. Specifically, the
tubing 28B is again coupled to the bag 27 at one end and the second fill
target 20 at the other end, such that fluid in the bag is
able to be drawn through the tubing and into the second fill target 20 by way
of the needle 29B. In this example, the tubing 28B
again branches into two tubing and then converges again, but the two tubing
have a different inner diameter. For example, the
inner diameter of the tubing 28B is 1.6mm and 3.2 mm, respectively. In
addition, the outer diameter of the needle 29B is 3.0mm,
the inner diameter of the needle is 2.6mm, and the inner diameter of the pump
tubing is 1.6 mm.
[0050] Referring now to FIG. 2E, an exemplary fill target is depicted. In
particular, the exemplary fill target may include the first
and second fill targets 18, 20 of FIG. 1, for example. In this example, the
first and second fill targets 18, 20 include a 1.3 mL fil in
ISO 2R vial. For this exemplary fill target, the target weight is 1.365 grams,
T2+ is 0.05gram5, which is 1.415 grams, and T2- is
0.05 grams, which is 1.315 grams. Also, T1+ is 0.03 grams, which is 1.395
grams, and Ti- is 0.03 grams, which is 1.335 grams.
Further, the net weight no adjustment limit + is 0.02 grams, which is 1.385
grams, and the net weight no adjustment limit ¨ is 0.02
grams, which is 1.345 grams.
[0051] Referring now to FIG. 3A, a chart depicting exemplary parameters of
the first and second fill sets 14, 16 of FIG. 1, for
example, is depicted. As indicated in the chart, and in this example, the
first fill set 14 is a peristaltic pump filling assembly
having a needle with an outer diameter of 2.0mm and an inner diameter of
1.6mm. In addition, the peristaltic pump filling
assembly includes tubing (in FIG. 2C) having an inner diameter of 1.6mm. The
chart in FIG. 3A also includes information about
the second fill set 16, which in this example also includes a peristaltic pump
filling assembly having a needle with an outer
diameter of 2.0mm and an inner diameter of 2.6mm. Like the first fill set 14,
the second fill set 16 also includes tubing having an
inner diameter of 1.6mm, and another tubing having an inner diameter of 3.2mm,
as mentioned above.
[0052] Referring now to FIG. 3B, various in process control parameters were
initially set on the second fill set 16. In particular,
a no adjustment limit for a fill weight of the second fill target 20, such as
the vial, was set to Ti, with Ti being at or in a range of
about 2% more or 2% less than a fill weight of a target fill weight TO.
Specifically, and in one example provided in the chart in
FIG. 3B, the target fill weight TO includes a volume of 1.3 mL and a mass of
1.365 grams. In this example, the no adjustment
limit was 80% of Ti, which may be +/- 0.02 grams of Ti +/- 0.03 grams. Thus,
the fill target mass of a vial in which no
adjustment is needed is any value in the range of 1.345 grams to 1.385 grams
in this example. In another example, the no
adjustment limit for a fill weight of the vial, such as the second fill target
20, may be set to any value within a range of a target fill
weight TO and Ti, with Ti being at or in a range between the target fill
weight TO and T2 based on process performance, for
example. In some examples, Ti is set at 2%, but may be changed.
[0053] Referring now to FIG. 3C, a chart listing parameters of various drug
products initially used in the optimization process is
depicted. In particular, the filling recipe of the present disclosure includes
filling a vial, such as the vials of the first and second
filling targets 18, 20, with a drug product via a pump, and the drug product
includes a mAb formulation. In this example, the mAb
formulations used are drug product 1 (DP1) and drug product 1 (DP2) As
provided in the chart, at 5 degrees Celsius the density
of DP1 is 1.055 g/cm3 and the viscosity is 4.857. At 25 degrees Celsius, the
density of DP1 is 1.05 g/cm3, the viscosity is 2.604
cP, and the surface tension is 41.63 mN/m . At 5 degrees Celsius the density
of DP2 is 1.054 g/cm3 and the viscosity is 4.07
cP. In addition, at 25 degrees Celsius, the density of DP2 is 1.049 g/cm3, the
viscosity is 2.19 cP, and the surface tension is
43.716 mN/m . Thus, in this example, the drug product used in the filling
recipe is a mAb formulation including one or more of:
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(1) a density in a range of either about 1.054-1.055 g/cm3 at 5 degrees
Celsius or about 1.049-1.05 g/cm3at 25 degrees Celsius;
(2) a viscosity in a range of either about 4.07-4.857 cP at 5 degrees Celsius
or about 2.19-2.604 cP at 25 degrees Celsius, and a
surface tension in a range of about 41.00-43.80 mN/m at 25 degrees Celsius.
[0054] The method disclosed herein can be used to fill any liquid drug
product, such as drug products comprising a biologic
drug (e.g., peptides, mAbs, siRNAs) and a small molecule drug, provided the
drug product has a specified physical parameter
range. More specifically, and in one example, the drug product may include one
or more of the following characteristics: (1) a
density in a range of about 1.0-1.2 g/cm3; and/or (2) a viscosity in a range
of about 1.0-10.0 cP; and/or (3) a surface tension in a
range of about 40.0-72.7 mN/m. In one example, preferred ranges for the
viscosity are one or more of 1.0-8.0 cP, 1.0-6.0 cP,
1.0-5.0 cP, and 1.0-4.0 cP. In another example, the drug product has a density
in a range of 1.0-1.2 g/cm3; a viscosity in a range
of about 1.0-10.0 cP; and a surface tension in a range of about 40.0-72.7
mN/m. In another example, the drug product has one or
more of a density in a range of 1.0-1.2 g/cm3 and a viscosity in a range of
about 1.0-10.0 cP, and any value for a surface tension.
Said another way, in one example, the determining factors for the filling
recipe are the density and the viscosity of the drug
product, and the filling recipe may work with any surface tension. It will be
understood that a drug product meeting any of these
parameters may be used with the methods and filling recipe of the present
disclosure.
[0055] For example, in one example, manufacturing data suggests that a drug
product with a viscosity of about 8.0 cP or more
worked well with a drip retraction value of 20 degrees. In addition, in
another example, the preferred density of the drug product
is about 1.0-1.1 g/cm3. It will be appreciated that many other values within
the density, viscosity, and surface tension ranges
provided above may be used for the drug products used with the methods and
filling recipes of the present disclosure and fall
within the scope of the present disclosure.
[0056] Referring now to FIG. 4, a flow chart depicting a fill parameter
optimization strategy for the drug product DP1 is
provided. Specifically, in step 30 an initial optimization based on an
existing filling recipe, which is referred to as existing filling
recipe No. 1, was conducted on the second fill set 16. Next, in step 32, with
this initially optimized DP1 filling recipe for the
second fill set 16, a range of drip retraction parameters ranging from 0
degrees to 45 degrees was tested. In step 34, another
existing filling recipe, referred to as existing filling recipe No. 2, was
started and a range of drip retraction parameters from 10
degrees to 20 degrees was tested. A hybrid of existing filling recipe No. 1
and existing filling recipe No. 2 was then developed in
step 36 and various drip retraction parameters were also tested, including 5
degrees, 10 degrees and 20 degrees. In step 38,
the hybrid recipe was finalized for the second fill set 16 with a drip
retraction parameter set at 20 degrees. Lastly, in step 40, the
same filling recipe was used for the first fill set 14 and drip retraction
parameters were set at 10 degrees and 20 degrees. Based
on the fill performance, a filling recipe for the first fill set 14 was
finalized with a drip retraction parameter set at 20 degrees.
[0057] Referring now to FIG. 5A, fill performance results of the second
fill target 20, such as the vial, of the second fill set 16
after utilizing a filling recipe with various drip retraction values is
provided. In particular, a test was conducted and the fill
performance of the vial monitored when the drip retraction parameter of the
filling recipe for the pump was set to each of 0
degrees, 10 degrees, 20 degrees, 30 degrees, 40 degrees, and 45 degrees. As
noted in FIG. 5A, an air gap AG in the fill target
20 or vial increased with increasing drip retraction parameter leading to an
air liquid bilayer, explaining a likely reason for poor fill
performance when a higher drip retraction parameter is set in the filling
recipe. As noted in the chart of FIG. 5B, while the drip
retraction parameter set was different for each of the vials provided, all of
the other parameters for the filling recipe used in these
experiments were the same. In particular, the start pump dosing was set at 40
degrees, the pump dosing start ramp was set at
90 degrees, the pump dosing stop ramp was set at 210 degrees, the end pump
dosing was set at 260 degrees, the end drip
retraction was set at 310 degrees, and the distance run per dose was 766
degrees.
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[0058] Referring now to FIG. 6A, a filling recipe including many of the
same constant parameters in the optimization cycles
documented in part in FIG. 5B, for example, is depicted, but with the drip
retraction parameter set at 20 degrees for the second fill
set 16. In particular, in the filling recipe, the start pump dosing was set at
40 degrees, the pump dosing start ramp was set at 90
degrees, the pump dosing stop ramp was set at 210 degrees, the end pump dosing
was set at 260 degrees, the end drip
retraction was set at 290 degrees, and the distance run per dose was 766
degrees.
[0059] Referring now to FIGS. 6B and 6C, the impact of the drip retraction
parameter set at 20 degrees on fill performance of
DP1 in the second fill set 16 is provided. Specifically, for 103 number of
fills on the second fill set 16 using the filling recipe set
forth in FIG. 6A, the minimum filling weight was 1.348 grams and the maximum
filling weight was 1.384 grams, making the
average fill weight 1.366 grams, with a standard deviation of 0.006. The
process performance index Cpk value was 2.69, which
is considerably higher than experiments using a filling recipe with the same
parameters except for the drip retraction parameter of
45 degrees. Said another way, the process performance index was much higher
when the drip retraction parameter was set to
20 degrees compared to higher values, such as 45 degrees, further indicating
the impact of the drip retraction parameter on the
fill performance.
[0060] Generally, the process performance index Cpk provides a value
indicative of the efficiency of a particular process. In
this example, the process performance index value Cpk relates to how close an
actual fill weight of a container, such as a vial, is
to a target fill weight. In addition, the process performance index value Cpk
also relates to how close each subsequent fill rate of
the additional containers, e.g., vials, are to each other. If there is a high
number of the process performance index value Cpk, a
given pump is providing an optimal performance. Likewise, a low number for the
process performance index value Cpk indicates
the pump is poorly performing. As it is important to fill a consistent dose of
a drug product in each container (e.g., vial) during a
manufacturing process, the higher the process performance index value Cpk,
which is also indicative of the consistency of the
filling process, is a critical value to the success of efficiently and
accurately filling vials.
[0061] Referring now to FIGS. 7A and 7B, based on the optimization cycles and
experimental data described above relative to
a filling recipe for the exemplary drug product DP1 in the second fill set 16,
a universal filling recipe 50 of the present disclosure
was finalized for each of the offline manufacturing system 10 of FIG. 1 and a
manufacturing line 102 of a manufacturing plant 100
of FIG. 12, as explained more below. In particular, and as set forth in FIG.
7A, the filling recipe 50 includes specific needle
parameters, including setting a needle setting dimension to one of 134.5 mm
and 39.0 mm, setting a basic needle position to 7.0
mm, and setting the start needle down to 25 degrees. In addition, the needle
parameters for the filling recipe 50 also include
setting the needle at a dosing start of 10 mm, setting the needle down to one
of 60 degrees and 23 degrees, and setting the
needle up at 125 degrees. Further, the filling recipe 50 also includes setting
the needle at the end of dosing to 13.0 mm and 310
degrees, setting the start needle to cut-off position of 315 degrees, setting
the cut off position reached to 13.0 mm and 315
degrees, setting the start needle to a basic position of 315 degrees, and the
basic needle position reached to 359 degrees.
[0062] In addition, and as set forth in FIG. 7B, the finalized filling
recipe 50 of the present disclosure also includes setting
several parameters for the pump. In particular, the filling recipe 50 includes
setting the start pump dosing to 40 degrees, setting
the pump dosing start ramp to 90 degrees, setting the pump dosing stop ramp to
210 degrees, and setting the end pump dosing
to 260 degrees. Further, the filling recipe includes setting the drip
retraction parameter to 20 degrees, such as the pump distance
run for the drip retraction to 20 degrees, the end drip retraction parameter
to 290 degrees, and the distance run per dose
parameter to 766 degrees. In another example, and more generally, the filling
recipe 50 may include setting the drip retraction
parameter to any value equal to or less than 20 degrees and still fall within
the scope of the present disclosure. In one example,
the lowest vai;.ie of the dr0 retraction parameter. is 0 degrees. In another
example, the filling recipe 50 may include setting the
drip retraction parameter for the pump to one of 10 degrees, 20 degrees, or
any value in a range of 10 degrees to 20 degrees.
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8
Still further, the filling recipe 50 may include setting the end drip
retraction to 290 degrees when the drip retraction parameter is
set to 20 degrees, or setting the end drip retraction value to 280 when
setting the drip retraction parameter to 10 degrees, for
example. Said another way, depending upon the value selected for the drip
retraction parameter, e.g., any value equal to or less
than 20 degrees, the end drip retraction parameter will be adjusted and set
accordingly to be consistent with the set drip
retraction parameter value. In addition, the finalized filling recipe 50 also
includes setting a no adjustment limit for the fill weight
of any vial to Ti, with Ti being at or in a range of about 2% more or 2% less
than a fill weight of a target fill weight TO, as
explained above relative to FIG. 3B, for example.
[0063] While this filling recipe 50 was finalized for the exemplary drug
product DP1 in the second fill set 16, the same filling
recipe 50 may also be used for the first fill set 14 using DP1 or other drug
products in the mAb formulation programs, for
example. Still further, and as explained more below, the same finalized
filling recipe 50 is also effectively used for a nested
syringe and vial line of a manufacturing plant. More generally, the method of
optimizing a filling recipe for a nested syringe and
vial line or other manufacturing line in a manufacturing plant includes using
the first and second fill sets 14, 16 of the offline
manufacturing system 1 of FIG. 1, for example.
[0064] Referring now to FIGS. 8A and 8B, the impact of temperature on fill
performance of the second fill set 16 was evaluated
for efficacy and the results are provided in the graph of FIG. 8A and the
table of FIG. 8B. In particular, for this experimental
cycle, the temperature was set at 10-11 degrees Celsius and the process
performance parameter Cpk during this temperature
range of 10-11 degrees Celsius throughout the fill cycle well exceeded a
minimum value of 1.33. In particular, the cycle included
103 fills, with a minimum fill weight of 1.340 g, a maximum fill weight of
1.393 g, and an average fill weight of 1.362 g with a
standard deviation of 0.008 grams. Further, the process performance parameter
Cpk value was 1.95, well above the target
minimum value of 1.33, for example. While FIG. 8A shows that occasional
filling weights were close to the Ti limits at this
temperature range, subsequent fill weights were able to return close to the
target without significantly impacting the process
performance index Cpk.
[0065] Referring now to FIGS. 9A and 9B, the impact of a temperature higher
than 10-11 degrees Celsius (as in FIGS. 8A and
8B) on fill performance of the second fill set 16 was evaluated, and the
results are provided in the graph of FIG. 9A and the table
of FIG. 9B. In particular, for this experimental cycle, the temperature was
set at about 19 degrees Celsius, and the process
performance parameter Cpk during this temperature of about 19 degrees Celsius
throughout the fill cycle well exceeded a
minimum value of 1.33. Specifically, the cycle included 103 fills, with a
minimum fill weight of 1.348 g, a maximum fill weight of
1.384 g, and an average fill weight of 1.366 g with a standard deviation of
0.006 grams. Further, the process performance
parameter Cpk against T2 was 2.69, well above both the target minimum value of
1.3, and the process performance parameter
Cpk for the fill performance at the lower temperature of 10-11 degrees
Celsius, in this example. This indicates an even better fill
performance for the finalized filling recipe at slightly higher temperatures.
[0066] Referring now to FIGS. 10A and 10B, the impact of a temperature on
fill performance of the first fill set 14 was
evaluated, and the results are provided in the graph of FIG. 10A and the table
of FIG. 10B. In particular, for this experimental
cycle, the temperature was set at about a range of 10-11 degrees Celsius, and
the process performance parameter Cpk during
this temperature throughout the fill cycle well exceeded a minimum value, such
as 1.33. Specifically, the cycle included 100 fills,
with a minimum fill weight of 1.354 g, a maximum fill weight of 1.380 g, and
an average fill weight of 1.365 g with a standard
deviation of 0.005 grams. Further, the process performance parameter Cpk
against T2 was 3.16, well above each of the target
minimum value of 1.33, and the process performance parameter Cpk for the fill
performance of the second fill set 16 at both the
lower temperature of 10-11 degrees Celsius (FIGS. 8A and 8B) and the higher
temperature 19 degrees Celsius (FIGS. 9A and
9B), for example. Thus, such results further show the universal nature and
applicability of the finalized filling recipe on different
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9
fill sets, and this filling recipe may also be successfully transferred and
used with a nested syringe and vial line of a
manufacturing plant, for example.
[0067] Referring now to FIGS. 11A and 11B, the impact of a temperature
higher than 10-11 degrees Celsius (as in FIGS. 10A
and 10B) on fill performance of the first fill set 14 was evaluated, and the
results are provided in the graph of FIG. 11A and the
table of FIG. 11B. In particular, for this experimental cycle, the temperature
was set at about 19 degrees Celsius and the process
performance parameter Cpk during this temperature of about 19 degrees Celsius
throughout the fill cycle well exceeded a
minimum value of 1.33. Specifically, the cycle included 120 fills, with a
minimum fill weight of 1.352 g, a maximum fill weight of
1.373 g, and an average fill weight of 1.362 g with a standard deviation of
0.004 grams. Further, the process performance
parameter Cpk against T2 was 3.61, well above both the target minimum value of
1.33, and the process performance parameter
Cpk of 3.16 for the fill performance at the lower temperature of 10-11 degrees
Celsius, for example.
[0068] Thus, the results show that there is superior fill weight performance
with the first set 14 of FIGS. 10A-11B compared to
the fill performance of the second fill set 16 of FIGS. 8A-9B, although the
minimum process performance index Cpk is exceeded
for all temperature ranges of both the first and second sets 14, 16. In
addition, the temperature effect observed with the second
fill set 16 is less pronounced in the first fill set 14.
[0069] Referring now to FIG. 12, a schematic representation of a
manufacturing line 102 in a manufacturing plant 100 is
depicted. In this example, the manufacturing line 102 includes at least one
nested syringe and vial line 104 in which the efficient
universal filling recipe 50 of the present disclosure is effectively used. In
one example, the nested syringe and vial line 104 is a
nested syringe and vial line (NSVL) having a plurality of vials 105, such as
ISO 2R RTU vials. It will be understood that the filling
recipe 50 of the present disclosure may be utilized in a variety of other
nested syringe and vial lines and still fall within the scope
of the present disclosure. It will also be understood that the vial 105 may
more generally be any container 105, such as a
syringe, and still fall within the scope of the present disclosure. In
addition, in other examples, the manufacturing line 102 may
include a plurality of nested syringe and vial lines 106, each of which
includes the at least one nested syringe and vial line 104,
for example. The manufacturing line 102 also includes at least one pump 110
that corresponds to and cooperates with at least
one vial of the at least one nested syringe and vial line 104. In addition,
there may also be a plurality of pumps 112 that
correspond to a plurality of vials 114 of the nested syringe and vial line
104. In still other examples, there may be a plurality of
nested syringe and vial lines in which the filling recipe 50 of the present
disclosure is implemented.
[0070] Referring now to FIGS. 13A and 13B, an exemplary nested syringe and
vial line 104 of FIG. 12 is depicted in FIG. 13A.
The nested syringe and vial line 104 is a B20 nested syringe and vial line
(NSVL) that includes a semi-automated debagger
104a, an automated debagger 104b, a rapid transfer airlock 104c, a nested
filler (isolator) 104d, and a capper 104e. Various
other clinical or commercial manufacturing fillers may alternatively be used
and still fall within the scope of the present disclosure.
[0071] In addition, FIG. 13B depicts a plurality of pumps, which may be the
plurality of pumps 112 that correspond to the
plurality of vials 114 of the nested syringe and vial line 104 of FIG. 12, for
example. In this example, the plurality of pumps 112
include five pumps 110 that cooperate with each vial 105 of the plurality of
vials 114. In this example, the nested syringe and vial
line 104 is a clinical manufacturing filler, such a Bausch & Strobel filler.
While the containers 105 are referred to generally as
vials, it will be understood that the containers 105 may be one or more of
vials, syringes or plastic cartridges and still fall within
the scope of the present disclosure. For example, the containers 105 may
include nested ISO 2R vials, nested 1mL glass and
plastic syringes, or nested 5cc plastic cartridges. In addition, while the
plurality of pumps include five pumps 110 in this
example, it will be understood that more or fewer pumps may alternatively be
used and still fall within the scope of the present
disclosure. In one example, the plurality of pumps may include 10 pumps or 2
pumps for different filler, or any other number of
pumps within this range, for example, and still fall within the scope of the
present disclosure.
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[0072] A method of filling the plurality of vials 105 of the nested syringe
and vial line 104 comprises providing one of the pump
110 or a plurality of pumps 112 corresponding to one of the vial 105 or the
plurality of vials 105 of the nested syringe and vial line
104. The method also includes setting the drip retraction parameter for each
pump 110 to any value equal to or less than 20
degrees. In addition, in one example, the method also includes setting a no
adjustment limit for the fill weight of the vial 105 to
Ti, with Ti being at or in a range of about 2% more or 2% less than the fill
weight of the target fill weight TO. The method may
still further include filling each vial 105 of the plurality of vials 105 with
a drug product, such as a mAb formulation, via a
corresponding pump 110 of the plurality of pumps 112. The method may still
also include exceeding a minimum value for the
process performance index Cpk for each vial 105 of the plurality of vials 105
during a temperature range throughout a fill cycle,
the temperature range one of: (1) 5 (+/-3) degrees Celsius; (2) 20 (45) degree
Celsius; or (3) 10 to 19 degrees Celsius.
[0073] In this example, the minimum value for the process performance index
Cpk is 1.33. In other examples, such as in
clinical fills, a minimum value for the process performance index Cpk is 1Ø
However, in this example, and as generally
understood in commercial fills, the minimum value for the process performance
index Cpk is 1.33. In addition, filling each vial 105
with the drug product via the corresponding pump 110 of the plurality of pumps
112 comprises filling each vial 105 with a drug
product, wherein the drug product has one or more of the following
characteristics: (1) a density in a range of about 1.0-1.2
g/cm3; (b) a viscosity in a range of about 1.0-10.0 cP; and (c) a surface
tension in a range of about 40.0-72.7 mN/m. In one
example, the drug product has a density in a range of 1.0-1.2 g/cm3; a
viscosity in a range of about 1.0-10.0 cP; and a surface
tension in a range of about 40.0-72.7 mN/m.
[0074] Referring now to FIGS. 14 and 15, the fill performance of the new
filling recipe of the present disclosure in the nested
syringe and vial line 104 is provided. In particular, using the new filling
recipe, the total dose optimization cycle, such as the
number of strokes of the pump 110 (or pumps 112) needed to teach the pump 110
how to operate using the new filling recipe is
minimized. Specifically, the total dose optimization cycle value is 4, which
is significantly reduced compared to values of the total
dose optimization cycle of previous filling recipes set forth in FIG. 15, for
example. In addition, the process performance index
Cpk for each nozzle (not shown) of each pump 110 of the plurality of pumps 112
of the nested syringe and vial 1ine104 (of FIG.
12) exceeds the minimum value of 1.33 for the process performance index Cpk
desired. In fact, the average process
performance index Cpk value for all nozzles of the pumps 110 is 1.4.
[0075] Referring now to FIG. 15, a chart listing the process performance
index Cpk of nozzles of the pumps using old filling
recipes is set forth. Specifically, when using old filling recipes for a large
variety of different drug products, including the mAb
formulations, the average process performance index Cpk for all nozzles of the
pumps was well below the desired process
performance index Cpk value of 1.33. Said another way, all of the process
performance index Cpk values were less than 1.33.
In addition, the total dose optimization cycle was greater for each drug
product using the old filling recipe compared to the dose
optimization cycle value listed in FIG. 14 when using the new filling recipe
50.
[0076] In view of the foregoing, it will be appreciated that a method of
optimizing a filling recipe for a container, such as the vial
105 of the nested syringe and vial line 104, was finalized using the first and
second fill sets 14, 16 and corresponding first and
second fill targets 18, 20 of an offline manufacturing system 10 described
above and depicted in FIG. 1, for example. By
finalizing the recipe using an offline system, such as the offline system 10,
a team of scientists is able to run experiments and
tests unable to be conducted in a large scale manufacturing plant such that
the manufacturing line within the manufacturing plant
is not displaced or interrupted. In addition, the offline systems 10 often
include cameras and do not include the limitations of
needed operator gear and other restrictions of a large-scale manufacturing
plant. Further, this same optimized filling recipe may
be used for different drug products, as described above.
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[0077] More specifically, the method of optimizing the filling recipe for
the nested syringe and vial line 104 includes setting the
drip retraction parameter for at least one pump 14, 16, 22 in the offline
manufacturing system 10 corresponding to at least one
container 18, 20 to any value equal to or less than 20 degrees. The method
further includes monitoring a performance of the at
least one pump 14, 16, 20 with the drip retraction parameter of the at least
one pump 14, 16, 22 set to any value equal to or less
than 20 degrees. The method still further includes obtaining at least a
minimum value for the process performance index (Cpk)
for the at least one container 18, 20 throughout at least one fill cycle and
for at least one drug product using the at least one
pump 14, 16, 22 in the offline manufacturing system 10. The method also
includes finalizing a filling recipe for the nested syringe
and vial line 104 using data from fill cycles of the at least one drug product
using the at least one pump 14, 16, 22 in the offline
manufacturing system 10.
[0078] Thus, an optimized filling recipe for drug products, such as mAb drug
products, has been developed that is applicable
to manufacturing lines in a manufacturing plant. As a result, significant time
related to programming of pumps corresponding to a
nested syringe and vial line of the manufacturing plant (e.g., often needed
for different recipes for different drug products) is
saved.
[0079] The above description describes various systems and methods of
filling a vial of a nested syringe and vial line. It
should be clear that the system or methods can further comprise use of a
medicament listed below with the caveat that the
following list should neither be considered to be all inclusive nor limiting.
The medicament will be contained in a reservoir. In
some instances, the reservoir is a primary container that is either filled for
treatment with the medicament. The primary container
can be a vial, a cartridge or a syringe.
[0080] For example, drug products that may be used with the methods disclosed
herein may include colony stimulating
factors, such as granulocyte colony-stimulating factor (G-CSF). Such G-CSF
agents include, but are not limited to, Neupogen@
(filgrastim) and Neulasta@ (pegfilgrastim). In various other embodiments, the
methods may use various pharmaceutical
products, such as an erythropoiesis stimulating agent (ESA), which may be in a
liquid or a lyophilized form. An ESA is any
molecule that stimulates erythropoiesis, such as Epogen@ (epoetin alfa),
Aranesp@ (darbepoetin alfa), Dynepo@ (epoetin delta),
Mircera@ (methyoxy polyethylene glycol-epoetin beta), Hematide@, MRK-2578, INS-
22, Retacrit@ (epoetin zeta), Neorecormon@
(epoetin beta), Silapo@ (epoetin zeta), Binocrit@ (epoetin alfa), epoetin alfa
Hexal, Abseamed@ (epoetin alfa), Ratioepo@
(epoetin theta), Eporatio@ (epoetin theta), Biopoin@ (epoetin theta), epoetin
alfa, epoetin beta, epoetin zeta, epoetin theta, and
epoetin delta, as well as the molecules or variants or analogs thereof as
disclosed in the following patents or patent applications,
each of which is herein incorporated by reference in its entirety: U.S. Patent
Nos. 4,703,008; 5,441,868; 5,547,933; 5,618,698;
5,621,080; 5,756,349; 5,767,078; 5,773,569; 5,955,422; 5,986,047; 6,583,272;
7,084,245; and 7,271,689; and PCT Publication
Nos. WO 91/05867; WO 95/05465; WO 96/40772; WO 00/24893; WO 01/81405; and WO
2007/136752.
[0081] An ESA can be an erythropoiesis stimulating protein. As used herein,
"erythropoiesis stimulating protein" means any
protein that directly or indirectly causes activation of the erythropoietin
receptor, for example, by binding to and causing
dimerization of the receptor. Erythropoiesis stimulating proteins include
erythropoietin and variants, analogs, or derivatives
thereof that bind to and activate erythropoietin receptor; antibodies that
bind to erythropoietin receptor and activate the receptor;
or peptides that bind to and activate erythropoietin receptor. Erythropoiesis
stimulating proteins include, but are not limited to,
epoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin iota,
epoetin zeta, and analogs thereof, pegylated
erythropoietin, carbamylated erythropoietin, mimetic peptides (including
EMP1/hematide), and mimetic antibodies. Exemplary
erythropoiesis stimulating proteins include erythropoietin, darbepoetin,
erythropoietin agonist variants, and peptides or antibodies
that bind and activate erythropoietin receptor (and include compounds reported
in U.S. Publication Nos. 2003/0215444 and
2006/0040858, the disclosures of each of which is incorporated herein by
reference in its entirety) as well as erythropoietin
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12
molecules or variants or analogs thereof as disclosed in the following patents
or patent applications, which are each herein
incorporated by reference in its entirety: U.S. Patent Nos. 4,703,008;
5,441,868; 5,547,933; 5,618,698; 5,621,080; 5,756,349;
5,767,078; 5,773,569; 5,955,422; 5,830,851; 5,856,298; 5,986,047; 6,030,086;
6,310,078; 6,391,633; 6,583,272; 6,586,398;
6,900,292; 6,750,369; 7,030,226; 7,084,245; and 7,217,689; U.S. Publication
Nos. 2002/0155998; 2003/0077753;
2003/0082749; 2003/0143202; 2004/0009902; 2004/0071694; 2004/0091961;
2004/0143857; 2004/0157293; 2004/0175379;
2004/0175824; 2004/0229318; 2004/0248815; 2004/0266690; 2005/0019914;
2005/0026834; 2005/0096461; 2005/0107297;
2005/0107591; 2005/0124045; 2005/0124564; 2005/0137329; 2005/0142642;
2005/0143292; 2005/0153879; 2005/0158822;
2005/0158832; 2005/0170457; 2005/0181359; 2005/0181482; 2005/0192211;
2005/0202538; 2005/0227289; 2005/0244409;
2006/0088906; and 2006/0111279; and PCT Publication Nos. WO 91/05867; WO
95/05465; WO 99/66054; WO 00/24893; WO
01/81405; WO 00/61637; WO 01/36489; WO 02/014356; WO 02/19963; WO 02/20034; WO
02/49673; WO 02/085940; WO
03/029291; WO 2003/055526; WO 2003/084477; WO 2003/094858; WO 2004/002417; WO
2004/002424; WO 2004/009627;
WO 2004/024761; WO 2004/033651; WO 2004/035603; WO 2004/043382; WO
2004/101600; WO 2004/101606; WO
2004/101611; WO 2004/106373; WO 2004/018667; WO 2005/001025; WO 2005/001136;
WO 2005/021579; WO 2005/025606;
WO 2005/032460; WO 2005/051327; WO 2005/063808; WO 2005/063809; WO
2005/070451; WO 2005/081687; WO
2005/084711; WO 2005/103076; WO 2005/100403; WO 2005/092369; WO 2006/50959; WO
2006/02646; and WO 2006/29094.
[0082] Examples of other pharmaceutical products that may be used with the
methods disclosed herein may include, but are
not limited to, antibodies such as Vectibix (panitumumab), Xgeva TM
(denosumab) and Prolia TM (denosamab); other biological
agents such as Enbrel (etanercept, TNF-receptor /Fc fusion protein, TNF
blocker), Neulasta (pegfilgrastim, pegylated
filgastrim, pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen (filgrastim ,
G-CSF, hu-MetG-CSF), and Nplate
(romiplostim); small molecule drugs such as Sensipar (cinacalcet). The
methods may also be used with a therapeutic antibody,
a polypeptide, a protein or other chemical, such as an iron, for example,
ferumoxytol, iron dextrans, ferric glyconate, and iron
sucrose. The pharmaceutical product may be in liquid form, or reconstituted
from lyophilized form.
[0083] Among particular illustrative proteins are the specific proteins set
forth below, including fusions, fragments, analogs,
variants or derivatives thereof: OPGL specific antibodies, peptibodies, and
related proteins, and the like (also referred to as
RAN KL specific antibodies, peptibodies and the like), including fully
humanized and human OPGL specific antibodies, particularly
fully humanized monoclonal antibodies, including but not limited to the
antibodies described in PCT Publication No. WO
03/002713, which is incorporated herein in its entirety as to OPGL specific
antibodies and antibody related proteins, particularly
those having the sequences set forth therein, particularly, but not limited
to, those denoted therein: 9H7; 1882; 2D8; 2E11; 16E1;
and 22B3, including the OPGL specific antibodies having either the light chain
of SEQ ID NO:2 as set forth therein in Figure 2
and/or the heavy chain of SEQ ID NO:4, as set forth therein in Figure 4, each
of which is individually and specifically incorporated
by reference herein in its entirety fully as disclosed in the foregoing
publication;
[0084] Myostatin binding proteins, peptibodies, and related proteins, and
the like, including myostatin specific peptibodies,
particularly those described in U.S. Publication No. 2004/0181033 and PCT
Publication No. WO 2004/058988, which are
incorporated by reference herein in their entirety particularly in parts
pertinent to myostatin specific peptibodies, including but not
limited to peptibodies of the mTN8-19 family, including those of SEQ ID
NOS:305-351, including TN8-19-1 through TN8-19-40,
TN8-19 con1 and TN8-19 c0n2; peptibodies of the mL2 family of SEQ ID NOS:357-
383; the mL15 family of SEQ ID NOS:384-
409; the mL17 family of SEQ ID NOS:410-438; the mL20 family of SEQ ID NOS:439-
446; the mL21 family of SEQ ID NOS:447-
452; the mL24 family of SEQ ID NOS:453-454; and those of SEQ ID NOS:615-631,
each of which is individually and specifically
incorporated by reference herein in their entirety fully as disclosed in the
foregoing publication;
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[0085] IL-4 receptor specific antibodies, peptibodies, and related
proteins, and the like, particularly those that inhibit activities
mediated by binding of IL-4 and/or IL-13 to the receptor, including those
described in PCT Publication No. WO 2005/047331 or
PCT Application No. PCT/US2004/37242 and in U.S. Publication No. 2005/112694,
which are incorporated herein by reference in
their entirety particularly in parts pertinent to IL-4 receptor specific
antibodies, particularly such antibodies as are described
therein, particularly, and without limitation, those designated therein: L1H1;
L1H2; L1H3; L1H4; L1H5; L1H6; L1H7; L1H8; L1H9;
L1H10; L1H11; L2H1; L2H2; L2H3; L2H4; L2H5; L2H6; L2H7; L2H8; L2H9; L2H10;
L2H11; L2H12; L2H13; L2H14; L3H1; L4H1;
L5H1; L6H1, each of which is individually and specifically incorporated by
reference herein in its entirety fully as disclosed in the
foregoing publication;
[0086] Interleukin 1-receptor 1 ("IL1-R1") specific antibodies,
peptibodies, and related proteins, and the like, including but not
limited to those described in U.S. Publication No. 2004/097712, which is
incorporated herein by reference in its entirety in parts
pertinent to IL1-R1 specific binding proteins, monoclonal antibodies in
particular, especially, without limitation, those designated
therein: 15CA, 26F5, 27F2, 24E12, and 10H7, each of which is individually and
specifically incorporated by reference herein in its
entirety fully as disclosed in the aforementioned publication;
[0087] Ang2 specific antibodies, peptibodies, and related proteins, and the
like, including but not limited to those described in
PCT Publication No. WO 03/057134 and U.S. Publication No. 2003/0229023, each
of which is incorporated herein by reference
in its entirety particularly in parts pertinent to Ang2 specific antibodies
and peptibodies and the like, especially those of
sequences described therein and including but not limited to: Li (N); Li (N)
WT; Li (N) 1K WT; 2xL1(N); 2xL1(N) WT; Con4 (N),
Con4 (N) 1K WT, 2xCon4 (N) 1K; Li C; L1C 1K; 2xL1C; Con4C; Con4C 1K; 2xCon4C
1K; Con4-L1 (N); Con4-L1C; TN-12-9 (N);
C17 (N); TN8-8(N); TN8-14 (N); Con 1 (N), also including anti-Ang 2 antibodies
and formulations such as those described in PCT
Publication No. WO 2003/030833 which is incorporated herein by reference in
its entirety as to the same, particularly Ab526;
Ab528; Ab531; Ab533; Ab535; Ab536; Ab537; Ab540; Ab543; Ab544; Ab545; Ab546;
A551; Ab553; Ab555; Ab558; Ab559;
Ab565; AbF1AbFD; AbFE; AbFJ; AbFK; AbG1D4; AbGC1E8; AbH1C12; AblA1; AblF;
AbIK, AblP; and AblP, in their various
permutations as described therein, each of which is individually and
specifically incorporated by reference herein in its entirety
fully as disclosed in the foregoing publication;
[0088] NGF specific antibodies, peptibodies, and related proteins, and the
like including, in particular, but not limited to those
described in U.S. Publication No. 2005/0074821 and U.S. Patent No. 6,919,426,
which are incorporated herein by reference in
their entirety particularly as to NGF-specific antibodies and related proteins
in this regard, including in particular, but not limited
to, the NGF-specific antibodies therein designated 4D4, 4G6, 6H9, 7H2, 14D10
and 14D11, each of which is individually and
specifically incorporated by reference herein in its entirety fully as
disclosed in the foregoing publication;
[0089] CD22 specific antibodies, peptibodies, and related proteins, and the
like, such as those described in U.S. Patent No.
5,789,554, which is incorporated herein by reference in its entirety as to
CD22 specific antibodies and related proteins,
particularly human CD22 specific antibodies, such as but not limited to
humanized and fully human antibodies, including but not
limited to humanized and fully human monoclonal antibodies, particularly
including but not limited to human CD22 specific IgG
antibodies, such as, for instance, a dimer of a human-mouse monoclonal hLL2
gamma-chain disulfide linked to a human-mouse
monoclonal hLL2 kappa-chain, including, but limited to, for example, the human
CD22 specific fully humanized antibody in
Epratuzumab, CAS registry number 501423-23-0;
[0090] IGF-1 receptor specific antibodies, peptibodies, and related
proteins, and the like, such as those described in PCT
Publication No. WO 06/069202, which is incorporated herein by reference in its
entirety as to IGF-1 receptor specific antibodies
and related proteins, including but not limited to the IGF-1 specific
antibodies therein designated Li Hi, L2H2, L3H3, L4H4, L5H5,
L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15,
L16H16, L17H17, L18H18, L19H19, L20H20,
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L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29,
L30H30, L31H31, L32H32, L33H33, L34H34,
L35H35, L36H36, L37H37, L38H38, L39H39, L40H40, L41H41, L42H42, L43H43,
L44H44, L45H45, L46H46, L47H47, L48H48,
L49H49, L50H50, L51H51, L52H52, and IGF-1R-binding fragments and derivatives
thereof, each of which is individually and
specifically incorporated by reference herein in its entirety fully as
disclosed in the foregoing publication;
[0091] Also among non-limiting examples of anti-IGF-1R antibodies for use in
the methods and compositions of the present
invention are each and all of those described in:
[0092] (i) U.S. Publication No. 2006/0040358 (published February 23, 2006),
2005/0008642 (published January 13, 2005),
2004/0228859 (published November 18, 2004), including but not limited to, for
instance, antibody 1A (DSMZ Deposit No. DSM
ACC 2586), antibody 8 (DSMZ Deposit No. DSM ACC 2589), antibody 23 (DSMZ
Deposit No. DSM ACC 2588) and antibody 18
as described therein;
[0093] (ii) PCT Publication No. WO 06/138729 (published December 28, 2006) and
WO 05/016970 (published February 24,
2005), and Lu et al. (2004), J. Biol. Chem. 279:2856-2865, including but not
limited to antibodies 2F8, Al2, and IMC-Al2 as
described therein;
[0094] (iii) PCT Publication No. WO 07/012614 (published February 1, 2007), WO
07/000328 (published January 4, 2007),
WO 06/013472 (published February 9, 2006), WO 05/058967 (published June 30,
2005), and WO 03/059951 (published July 24,
2003)
[0095] (iv) U.S. Publication No. 2005/0084906 (published April 21, 2005),
including but not limited to antibody 7C10, chimaeric
antibody C7C10, antibody h7C10, antibody 7H2M, chimaeric antibody *7C10,
antibody GM 607, humanized antibody 7C10
version 1, humanized antibody 7C10 version 2, humanized antibody 7C10 version
3, and antibody 7H2HM, as described therein;
[0096] (v) U.S. Publication Nos. 2005/0249728 (published November 10, 2005),
2005/0186203 (published August 25, 2005),
2004/0265307 (published December 30, 2004), and 2003/0235582 (published
December 25, 2003) and Maloney et al. (2003),
Cancer Res. 63:5073-5083, including but not limited to antibody EM164,
resurfaced EM164, humanized EM164, huEM164 v1.0,
huEM164 v1.1, huEM164 v1.2, and huEM164 v1.3 as described therein;
[0097] (vi) U.S. Patent No. 7,037,498 (issued May 2, 2006), U.S.
Publication Nos. 2005/0244408 (published November 30,
2005) and 2004/0086503 (published May 6, 2004), and Cohen, et al. (2005),
Clinical Cancer Res. 11:2063-2073, e.g., antibody
CP-751,871, including but not limited to each of the antibodies produced by
the hybridomas having the ATCC accession numbers
PTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA-2793, and antibodies
2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and
4.17.3, as described therein;
[0098] (vii) U.S. Publication Nos. 2005/0136063 (published June 23, 2005)
and 2004/0018191 (published January 29, 2004),
including but not limited to antibody 19D12 and an antibody comprising a heavy
chain encoded by a polynucleotide in plasmid
15H12/19D12 HCA (y4), deposited at the ATCC under number PTA-5214, and a light
chain encoded by a polynucleotide in
plasmid 15H12/19D12 LCF (k), deposited at the ATCC under number PTA-5220, as
described therein; and
[0099] (viii) U.S. Publication No. 2004/0202655 (published October 14,
2004), including but not limited to antibodies PINT-
6A1, PINT-7A2, PINT-7A4, PINT-7A5, PINT-7A6, PINT-8A1, PINT-9A2, PINT-11A1,
PINT-11A2, PINT-11A3, PINT-11A4, PINT-
11A5, PINT-11A7, PINT-11Al2, PINT-12A1, PINT-12A2, PINT-12A3, PINT-12A4, and
PINT-12A5, as described therein; each
and all of which are herein incorporated by reference in their entireties,
particularly as to the aforementioned antibodies,
peptibodies, and related proteins and the like that target IGF-1 receptors;
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[00100] B-7 related protein 1 specific antibodies, peptibodies, related
proteins and the like ("B7RP-1," also is referred to in the
literature as B7H2, ICOSL, B7h, and CD275), particularly B7RP-specific fully
human monoclonal IgG2 antibodies, particularly
fully human IgG2 monoclonal antibody that binds an epitope in the first
immunoglobulin-like domain of B7RP-1, especially those
that inhibit the interaction of B7RP-1 with its natural receptor, ICOS, on
activated T cells in particular, especially, in all of the
foregoing regards, those disclosed in U.S. Publication No. 2008/0166352 and
PCT Publication No. WO 07/011941, which are
incorporated herein by reference in their entireties as to such antibodies and
related proteins, including but not limited to
antibodies designated therein as follow: 16H (having light chain variable and
heavy chain variable sequences SEQ ID NO:1 and
SEQ ID NO:7 respectively therein); 5D (having light chain variable and heavy
chain variable sequences SEQ ID NO:2 and SEQ
ID NO:9 respectively therein); 2H (having light chain variable and heavy chain
variable sequences SEQ ID NO:3 and SEQ ID
NO:10 respectively therein); 43H (having light chain variable and heavy chain
variable sequences SEQ ID NO:6 and SEQ ID
NO:14 respectively therein); 41H (having light chain variable and heavy chain
variable sequences SEQ ID NO:5 and SEQ ID
NO:13 respectively therein); and 15H (having light chain variable and heavy
chain variable sequences SEQ ID NO:4 and SEQ ID
NO:12 respectively therein), each of which is individually and specifically
incorporated by reference herein in its entirety fully as
disclosed in the foregoing publication;
[00101] IL-15 specific antibodies, peptibodies, and related proteins, and
the like, such as, in particular, humanized monoclonal
antibodies, particularly antibodies such as those disclosed in U.S.
Publication Nos. 2003/0138421; 2003/023586; and
2004/0071702; and U.S. Patent No. 7,153,507, each of which is incorporated
herein by reference in its entirety as to IL-15
specific antibodies and related proteins, including peptibodies, including
particularly, for instance, but not limited to, HuMax IL-15
antibodies and related proteins, such as, for instance, 14687;
[00102] IFN gamma specific antibodies, peptibodies, and related proteins
and the like, especially human IFN gamma specific
antibodies, particularly fully human anti-IFN gamma antibodies, such as, for
instance, those described in U.S. Publication No.
2005/0004353, which is incorporated herein by reference in its entirety as to
IFN gamma specific antibodies, particularly, for
example, the antibodies therein designated 1118; 1118*, 1119; 1121; and 1121*.
The entire sequences of the heavy and light
chains of each of these antibodies, as well as the sequences of their heavy
and light chain variable regions and complementarity
determining regions, are each individually and specifically incorporated by
reference herein in its entirety fully as disclosed in the
foregoing publication and in Thakur et al. (1999), Mol. lmmunol. 36:1107-1115.
In addition, description of the properties of these
antibodies provided in the foregoing publication is also incorporated by
reference herein in its entirety. Specific antibodies
include those having the heavy chain of SEQ ID NO:17 and the light chain of
SEQ ID NO:18; those having the heavy chain
variable region of SEQ ID NO:6 and the light chain variable region of SEQ ID
NO:8; those having the heavy chain of SEQ ID
NO:19 and the light chain of SEQ ID NO:20; those having the heavy chain
variable region of SEQ ID NO:10 and the light chain
variable region of SEQ ID NO:12; those having the heavy chain of SEQ ID NO:32
and the light chain of SEQ ID NO:20; those
having the heavy chain variable region of SEQ ID NO:30 and the light chain
variable region of SEQ ID NO:12; those having the
heavy chain sequence of SEQ ID NO:21 and the light chain sequence of SEQ ID
NO:22; those having the heavy chain variable
region of SEQ ID NO:14 and the light chain variable region of SEQ ID NO:16;
those having the heavy chain of SEQ ID NO:21
and the light chain of SEQ ID NO:33; and those having the heavy chain variable
region of SEQ ID NO:14 and the light chain
variable region of SEQ ID NO:31, as disclosed in the foregoing publication. A
specific antibody contemplated is antibody 1119 as
disclosed in the foregoing U.S. publication and having a complete heavy chain
of SEQ ID NO:17 as disclosed therein and having
a complete light chain of SEQ ID NO:18 as disclosed therein;
[00103] TALL-1 specific antibodies, peptibodies, and the related proteins,
and the like, and other TALL specific binding
proteins, such as those described in U.S. Publication Nos. 2003/0195156 and
2006/0135431, each of which is incorporated
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herein by reference in its entirety as to TALL-1 binding proteins,
particularly the molecules of Tables 4 and 5B, each of which is
individually and specifically incorporated by reference herein in its entirety
fully as disclosed in the foregoing publications;
[00104] Parathyroid hormone ("PTH") specific antibodies, peptibodies, and
related proteins, and the like, such as those
described in U.S. Patent No. 6,756,480, which is incorporated herein by
reference in its entirety, particularly in parts pertinent to
proteins that bind PTH;
[00105] Thrombopoietin receptor ("TPO-R") specific antibodies, peptibodies,
and related proteins, and the like, such as those
described in U.S. Patent No. 6,835,809, which is herein incorporated by
reference in its entirety, particularly in parts pertinent to
proteins that bind TPO-R;
[00106] Hepatocyte growth factor ("HGF") specific antibodies, peptibodies,
and related proteins, and the like, including those
that target the HGF/SF:cMet axis (HGF/SF:c-Met), such as the fully human
monoclonal antibodies that neutralize hepatocyte
growth factor/scatter (HGF/SF) described in U.S. Publication No. 2005/0118643
and PCT Publication No. WO 2005/017107,
huL2G7 described in U.S. Patent No. 7,220,410 and 0A-5d5 described in U.S.
Patent Nos. 5,686,292 and 6,468,529 and in PCT
Publication No. WO 96/38557, each of which is incorporated herein by reference
in its entirety, particularly in parts pertinent to
proteins that bind HGF;
[00107] TRAIL-R2 specific antibodies, peptibodies, related proteins and the
like, such as those described in U.S. Patent No.
7,521,048, which is herein incorporated by reference in its entirety,
particularly in parts pertinent to proteins that bind TRAIL-R2;
[00108] Activin A specific antibodies, peptibodies, related proteins, and
the like, including but not limited to those described in
U.S. Publication No. 2009/0234106, which is herein incorporated by reference
in its entirety, particularly in parts pertinent to
proteins that bind Activin A;
[00109] TGF-beta specific antibodies, peptibodies, related proteins, and
the like, including but not limited to those described in
U.S. Patent No. 6,803,453 and U.S. Publication No. 2007/0110747, each of which
is herein incorporated by reference in its
entirety, particularly in parts pertinent to proteins that bind TGF-beta;
[00110] Amyloid-beta protein specific antibodies, peptibodies, related
proteins, and the like, including but not limited to those
described in PCT Publication No. WO 2006/081171, which is herein incorporated
by reference in its entirety, particularly in parts
pertinent to proteins that bind amyloid-beta proteins. One antibody
contemplated is an antibody having a heavy chain variable
region comprising SEQ ID NO:8 and a light chain variable region having SEQ ID
NO:6 as disclosed in the foregoing publication;
[00111] c-Kit specific antibodies, peptibodies, related proteins, and the
like, including but not limited to those described in U.S.
Publication No. 2007/0253951, which is incorporated herein by reference in its
entirety, particularly in parts pertinent to proteins
that bind c-Kit and/or other stem cell factor receptors;
[00112] OX4OL specific antibodies, peptibodies, related proteins, and the
like, including but not limited to those described in
U.S. Publication No. 2006/0002929, which is incorporated herein by reference
in its entirety, particularly in parts pertinent to
proteins that bind OX4OL and/or other ligands of the 0X40 receptor; and
[00113] Other exemplary proteins, including Activase@ (alteplase, tPA);
Aranesp@ (darbepoetin alfa); Epogen@ (epoetin alfa,
or erythropoietin); GLP-1, Avonex@ (interferon beta-1a); Bexxar@ (tositumomab,
anti-CD22 monoclonal antibody); Betaseron@
(interferon-beta); Campath@ (alemtuzumab, anti-CD52 monoclonal antibody);
Dynepo@ (epoetin delta); Velcade@ (bortezomib);
MLN0002 (anti- a4I37 mAb); MLN1202 (anti-CCR2 chemokine receptor mAb); Enbrel@
(etanercept, TNF-receptor /Fc fusion
protein, TNF blocker); Eprex@ (epoetin alfa); Erbitux@ (cetuximab, anti-EGFR /
HER1 / c-ErbB-1); Genotropin@ (somatropin,
Human Growth Hormone); Herceptin@ (trastuzumab, anti-HER2/neu (erbB2) receptor
mAb); Humatrope@ (somatropin, Human
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Growth Hormone); Humira@ (adalimumab); insulin in solution; Infergen
(interferon alfacon-1); Natrecor@ (nesiritide;
recombinant human B-type natriuretic peptide (hBNP); Kineret@ (anakinra);
Leukine@ (sargamostim, rhuGM-CSF);
LymphoCide@ (epratuzumab, anti-CD22 mAb); BenlystaTM (lymphostat B, belimumab,
anti-BlyS mAb); Metalyse@ (tenecteplase,
t-PA analog); Mircera@ (methoxy polyethylene glycol-epoetin beta); Mylotarg@
(gemtuzumab ozogamicin); Raptiva@
(efalizumab); Cimzia@ (certolizumab pegol, CDP 870); SolirisTM (eculizumab);
pexelizumab (anti-05 complement); Numax@
(MEDI-524); Lucentis@ (ranibizumab); Panorex@ (17-1A, edrecolomab); Trabio@
(lerdelimumab); TheraCim hR3 (nimotuzumab);
Omnitarg (pertuzumab, 2C4); Osidem@ (IDM-1); OvaRex@ (B43.13); Nuvion@
(visilizumab); cantuzumab mertansine (huC242-
DM1); NeoRecormon@ (epoetin beta); Neumega@ (oprelvekin, human interleukin-
11); Neulasta@ (pegylated filgastrim, pegylated
G-CSF, pegylated hu-Met-G-CSF); Neupogen@ (filgrastim , G-CSF, hu-MetG-CSF);
Orthoclone OKT3@ (muromonab-CD3, anti-
CD3 monoclonal antibody); Procrit@ (epoetin alfa); Remicade@ (infliximab, anti-
TNFa monoclonal antibody); Reopro@
(abciximab, anti-GPIlb/Ilia receptor monoclonal antibody); Actemra@ (anti-1L6
Receptor mAb); Avastin@ (bevacizumab), HuMax-
CD4 (zanolimumab); Rituxan@ (rituximab, anti-CD20 mAb); Tarceva@ (erlotinib);
Roferon-A0-(interferon alfa-2a); Simulect@
(basiliximab); Prexige@ (lumiracoxib); Synagis@ (palivizumab); 14687-CHO (anti-
1L15 antibody, see U.S. Patent No. 7,153,507);
Tysabri@ (natalizumab, anti-a4integrin mAb); Valortim@ (MDX-1303, anti-B.
anthracis protective antigen mAb); ABthrax TM ;
Vectibix0 (panitumumab); Xolair@ (omalizumab); ETI211 (anti-MRSA mAb); IL-1
trap (the Fc portion of human IgG1 and the
extracellular domains of both IL-1 receptor components (the Type I receptor
and receptor accessory protein)); VEGF trap (Ig
domains of VEGFR1 fused to IgG1 Fc); Zenapax@ (daclizumab); Zenapax@
(daclizumab, anti-IL-2Ra mAb); Zevalin@
(ibritumomab tiuxetan); Zetia@ (ezetimibe); Orencia@ (atacicept, TACI-Ig);
anti-CD80 monoclonal antibody (galiximab); anti-CD23
mAb (lumiliximab); BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF
antagonist); CNTO 148 (golimumab, anti-TNFa mAb);
HGS-ETR1 (mapatumumab; human anti-TRAIL Receptor-1 mAb); HuMax-CD20
(ocrelizumab, anti-CD20 human mAb); HuMax-
EGFR (zalutumumab); M200 (volociximab, anti-a581 integrin mAb); MDX-010
(ipilimumab, anti-CTLA-4 mAb and VEGFR-1
(IMC-18F1); anti-BR3 mAb; anti-C. difficile Toxin A and Toxin B C mAbs MDX-066
(CDA-1) and MDX-1388); anti-CD22 dsFv-
PE38 conjugates (CAT-3888 and CAT-8015); anti-CD25 mAb (HuMax-TAC); anti-CD3
mAb (NI-0401); adecatumumab; anti-
CD30 mAb (MDX-060); MDX-1333 (anti-IFNAR); anti-CD38 mAb (HuMax CD38); anti-
CD4OL mAb; anti-Cripto mAb; anti-CTGF
Idiopathic Pulmonary Fibrosis Phase I Fibrogen (FG-3019); anti-CTLA4 mAb; anti-
eotaxin1 mAb (CAT-213); anti-FGF8 mAb;
anti-ganglioside GD2 mAb; anti-ganglioside GM2 mAb; anti-GDF-8 human mAb (MY0-
029); anti-GM-CSF Receptor mAb (CAM-
3001); anti-HepC mAb (HuMax HepC); anti-IFNa mAb (MEDI-545, MDX-1103); anti-
IGF1R mAb; anti-IGF-1R mAb (HuMax-
Inflam); anti-IL12 mAb (ABT-874); anti-IL12/1L23 mAb (CNTO 1275); anti-IL13
mAb (CAT-354); anti-IL2Ra mAb (HuMax-TAC);
anti-1L5 Receptor mAb; anti-integrin receptors mAb (MDX-018, CNTO 95); anti-
IP10 Ulcerative Colitis mAb (MDX-1100); anti-LLY
antibody; BMS-66513; anti-Mannose Receptor/hCG8 mAb (MDX-1307); anti-
mesothelin dsFv-PE38 conjugate (CAT-5001); anti-
PD1mAb (MDX-1106 (ONO-4538)); anti-PDGFRa antibody (IMC-3G3); anti-TGFR mAb
(GC-1008); anti-TRAIL Receptor-2
human mAb (HGS-ETR2); anti-TWEAK mAb; anti-VEGFR/Flt-1 mAb; anti-ZP3 mAb
(HuMax-ZP3); NVS Antibody #1; and NVS
Antibody #2.
[00114] Also included can be a sclerostin antibody, such as but not limited to
romosozumab, blosozumab, or BPS 804
(Novartis). Further included can be therapeutics such as rilotumumab,
bixalomer, trebananib, ganitumab, conatumumab,
motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab,
NPLATE, PROLIA, VECTIBIX or XGEVA.
Additionally, included in the device can be a monoclonal antibody (IgG) that
binds human Proprotein Convertase Subtilisin/Kexin
Type 9 (PCSK9), e.g. U.S. Patent No. 8,030,547, U.S. Publication No.
2013/0064825, W02008/057457, W02008/057458,
W02008/057459, W02008/063382, W02008/133647, W02009/100297, W02009/100318,
W02011/037791, W02011/053759,
W02011/053783, W02008/125623, W02011/072263, W02009/055783, W02012/0544438,
W02010/029513, W02011/111007,
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W02010/077854, W02012/088313, W02012/101251, W02012/101252, W02012/101253,
W02012/109530, and
W02001/031007.
[00115] Also included can be talimogene laherparepvec or another oncolytic HSV
for the treatment of melanoma or other
cancers. Examples of oncolytic HSV include, but are not limited to talimogene
laherparepvec (U.S. Patent Nos. 7,223,593 and
7,537,924); OncoVEXGALV/CD (U.S. Pat. No. 7,981,669); OrienX010 (Lei et al.
(2013), World J. Gastroenterol., 19:5138-5143);
G207, 1716; NV1020; NV12023; NV1034 and NV1042 (Vargehes et al. (2002), Cancer
Gene Ther., 9(12):967-978).
[00116] Also included are TIMPs. TIMPs are endogenous tissue inhibitors of
metalloproteinases (TIMPs) and are important in
many natural processes. TI MP-3 is expressed by various cells or and is
present in the extracellular matrix; it inhibits all the major
cartilage-degrading metalloproteases, and may play a role in role in many
degradative diseases of connective tissue, including
rheumatoid arthritis and osteoarthritis, as well as in cancer and
cardiovascular conditions. The amino acid sequence of TIMP-3,
and the nucleic acid sequence of a DNA that encodes TI MP-3, are disclosed in
U.S. Patent No. 6,562,596, issued May 13, 2003,
the disclosure of which is incorporated by reference herein. Description of
TIMP mutations can be found in U.S. Publication No.
2014/0274874 and PCT Publication No. WO 2014/152012.
[00117] Also included are antagonistic antibodies for human calcitonin gene-
related peptide (CGRP) receptor and bispecific
antibody molecule that target the CGRP receptor and other headache targets.
Further information concerning these molecules
can be found in PCT Application No. WO 2010/075238.
[00118] Additionally, bispecific T cell engager (BiTE@) molecules, e.g.
BLINCYTO@ (blinatumomab), can be used in the
methods disclosed herein. Alternatively, included can be an APJ large molecule
agonist e.g., apelin or analogues thereof in the
device. Information relating to such molecules can be found in PCT Publication
No. WO 2014/099984.
[00119] In certain embodiments, the medicament comprises a therapeutically
effective amount of an anti-thymic stromal
lymphopoietin (TSLP) or TSLP receptor antibody. Examples of anti-TSLP
antibodies that may be used in such embodiments
include, but are not limited to, those described in U.S. Patent Nos.
7,982,016, and 8,232,372, and U.S. Publication No.
2009/0186022. Examples of anti-TSLP receptor antibodies include, but are not
limited to, those described in U.S. Patent No.
8,101,182. In particularly preferred embodiments, the medicament comprises a
therapeutically effective amount of the anti-TSLP
antibody designated as AS within U.S. Patent No. 7,982,016.
[00120] Although the foregoing methods, and elements thereof, have been
described in terms of exemplary embodiments,
they are not limited thereto. The detailed description is to be construed as
exemplary only and does not describe every possible
embodiment of the invention because describing every possible embodiment would
be impractical, if not impossible. Numerous
alternative embodiments could be implemented, using either current technology
or technology developed after the filing date of
this patent that would still fall within the scope of the claims defining the
invention.
[00121] It should be understood that the legal scope of the invention is
defined by the words of the claims set forth at the end
of this patent. The appended claims should be construed broadly to include
other variants and embodiments of same, which may
be made by those skilled in the art without departing from the scope and range
of equivalents of the devices, systems, methods,
and their elements.
