Note: Descriptions are shown in the official language in which they were submitted.
CA2886757
TREATMENT OF ANXIETY WITH ILla ANTAGONIST
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is claims priority from U.S. provisional patent
application number
61/709,741 filed on October 4, 2012.
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
[0002] Not applicable.
FIELD OF THE INVENTION
[0003] The invention relates generally to the fields of medicine, dermatology,
and
immunology_ More particularly, the invention relates to the use of antibodies
(Abs) which
specifically bind interleukin- la (IL-1a) to treat inflammatory skin diseases
as well as
psychiatric conditions.
BACKGROUND
[0004] Inflammatory skin disorders acne, rosacea, and psoriasis afflict many
millions of
people. While not usually lethal, these conditions can cause physical
discomfort and affect
emotional well-being. There are currently a large number of different
treatments for
inflammatory skin disorders including corticosteroids, vitamin D analogs, coal
tar, ultraviolet
light, retinoids, methotrexate, cyclosporine, hydroxyurea, antibiotics, and
biologic agents
such as TNFalpha inhibitors. While these therapies have proven useful for many
patients,
many cause undesirable side-effects and none are ideal for every situation_
SUMMARY
[0005] The invention is based on the discovery that a mAb that specifically
binds IL-1 a is
useful for treating acne vulgaris and various psychiatric conditions (such as
anxiety and poor
self-image).
[0006] Accordingly, the invention features a method of reducing the number of
acne lesions
in a human subject, as well as a method of treating a psychiatric condition
(e.g., anxiety,
depression, or poor self-image) in a human subject. These methods can include
the step of
administering to the subject a pharmaceutical composition including a
pharmaceutically
acceptable carrier and an amount of an agent that selectively binds IL-la
effective to reduce
to reduce the number of acne lesions or improve a psychiatric condition in the
subject. The
agent can be an anti-IL-1a antibody such as a monoclonal antibody (e.g., of
the IgG1
isotype), a monoclonal antibody that includes a complementarity determining
region of
MABpl, or MABpl.
1
Date Recue/Date Received 2021-01-15
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
[0007] Another aspect of the invention features a method of reducing skin
inflammation in a
human subject by administering to the subject a pharmaceutical composition
including a
phannaceutically acceptable carrier and an amount of an anti-IL-la Ab (or
other agent that
specifically and/or selectively binds IL-1a) effective to reduce a symptom of
skin
inflammation (e.g., redness, swelling, leukocyte infiltration, lesion
development, or lesion
number) in the subject by at least about 10% (e.g., at least 8, 9, 10, 15, 17,
20, 30, 40, 50, 60,
70, 80, 90, or 100%) as measured by any standard deimatological test. The anti-
IL-la Ab can
be a mAb such as an IgGl. The anti-IL-la Ab can be the mAb designated as MABp1
or a
mAb that includes one or more complementarity determining regions (CDRs) of
MABpl.
The pharmaceutical composition can he administered to the subject by
injection,
subcutaneously, intravenously, intramuscularly, or intradermally. In the
method, the dose can
be at least 0.25 (e.g., at least 0.2, 0.5, 0.75., 1, 2, 3, 4, or 5) mg/ml.
[0008] In other aspects, the invention includes use of an agent that
selectively binds IL-la to
treat acne and/or a psychiatric condition in the subject, and a pharmaceutical
composition for
treating acne and/or a psychiatric condition in the subject, the composition
comprising an
agent that selectively binds IL-In. In the foregoing, the agent can be an anti-
IL-la antibody
such as a monoclonal antibody (e.g., of the IgG1 isotype), or a monoclonal
antibody that
includes a CDR of MABpl, or MABpl.
[0009] Unless otherwise defined, all technical terms used herein have the same
meaning as
commonly understood by one of ordinary skill in the art to which this
invention belongs.
Commonly understood definitions of biological terms can be found in Rieger et
al., Glossary
of Genetics: Classical and Molecular, 5th edition, Springer-Verlag: New York,
1991; and
Lewin, Genes V, Oxford University Press: New York, 1994. Commonly understood
definitions of medical terms can be found in Stedman's Medical Dictionary,
27`h Edition,
Lippincott, Williams & Wilkins, 2000.
[0010] As used herein, an "antibody" or "Ab" is an immunoglobulin (Ig), a
solution of
identical or heterogeneous Igs, or a mixture of Igs. An "Ab" can also refer to
fragments and
engineered versions of Igs such as Fab, Fab', and F(ab')2 fragments; and
scFv's,
heteroconjugate Abs, and similar artificial molecules that employ Ig-derived
CDRs to impart
antigen specificity. A "monoclonal antibody- or "mAb- is an Ab expressed by
one clonal B
cell line or a population of Ab molecules that contains only one species of an
antigen binding
site capable of immunoreacting with a particular epitope of a particular
antigen. A
"polyclonal Ab" is a mixture of heterogeneous Abs. Typically, a polyclonal Ab
will include
myriad different Ab molecules which bind a particular antigen with at least
some of the
2
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
different Abs immunoreacting with a different epitope of the antigen. As used
herein, a
polyclonal Ab can be a mixture of two or more mAbs.
[0011] An "antigen-binding portion" of an Ab is contained within the variable
region of the
Fab portion of an Ab and is the portion of the Ab that confers antigen
specificity to the Ab
(i.e., typically the three-dimensional pocket formed by the CDRs of the heavy
and light
chains of the Ab). A "Fab portion" or "Fab region" is the proteolytic fragment
of a papain-
digested Ig that contains the antigen-binding portion of that 1g. A "non-Fab
portion" is that
portion of an Ab not within the Fab portion, e.g., an "Fe portion" or "Fe
region." A "constant
region" of an Ab is that portion of the Ab outside of the variable region.
Generally
encompassed within the constant region is the "effector portion" of an Ab,
which is the
portion of an Ab that is responsible for binding other immune system
components that
facilitate the immune response. Thus, for example, the site on an Ab that
binds complement
components or Fe receptors (not via its antigen-binding portion) is an
effector portion of that
Ab.
[0012] When referring to a protein molecule such as an Ab, "purified" means
separated from
components that naturally accompany such molecules. Typically, an Ab or
protein is purified
when it is at least about 10% (e.g., 9%, 10%, 20%, 30% 40%, 50%, 60%, 70%,
80%, 90%,
95%, 98%, 99%, 99.9%, and 100%), by weight, free from the non-Ab proteins or
other
naturally-occurring organic molecules with which it is naturally associated.
Purity can be
measured by any appropriate method, e.g., column chromatography,
polyacrylamide gel
electrophoresis, or IIPLC analysis. A chemically-synthesized protein or other
recombinant
protein produced in a cell type other than the cell type in which it naturally
occurs is
"purified."
[0013] By "bind", "binds", or "reacts with" is meant that one molecule
recognizes and
adheres to a particular second molecule in a sample, but does not
substantially recognize or
adhere to other molecules in the sample. Generally, an Ab that "specifically
binds" another
molecule has a Kid greater than about 105, 106, to', tos, to', 1010, 1011,
or 1012 liters/mole for
that other molecule. An Ab that "selectively binds" a first molecule
specifically binds the first
molecule at a first epitope but does not specifically bind other molecules
that do not have the
first epitope. For example, an Ab which selectively binds IL- I alpha
specifically binds an
epitope on IL-lalpha but does not specifically bind IL- lbeta (which does not
have the
epitope).
[0014] A "therapeutically effective amount" is an amount which is capable of
producing a
medically desirable effect in a treated animal or human (e.g., amelioration or
prevention of a
disease or symptom of a disease).
3
CA2886757
[0015] Although methods and materials similar or equivalent to those described
herein can be
used in the practice or testing of the present invention, suitable methods and
materials are
described below.
In the case of conflict, the present specification, including
definitions will control. In addition, the particular embodiments discussed
below are
illustrative only and not intended to be limiting.
DETAILED DESCRIPTION
[0016] The invention encompasses compositions and methods for reducing sldn
inflammation including ameliorating one or more symptoms of a dermatological
pathology in
a subject. The below described preferred embodiments illustrate adaptation of
these
compositions and methods. Nonetheless, from the description of these
embodiments, other
aspects of the invention can be made and/or practiced based on the description
provided
below.
10016A] Various embodiments of the claimed invention relate to a
pharmaceutical composition
comprising a pharmaceutically acceptable carrier and an anti-IL-la antibody
for use in reducing
anxiety in a human subject that has acne.
10016B1 Various embodiments of the claimed invention relate to use of an anti-
IL-la antibody to
reduce anxiety in a human subject that has acne.
[0016C] Various embodiments of the claimed invention relate to use of an anti-
IL-1a antibody in
the preparation of a medicament to reduce anxiety in a human subject that has
acne.
[0016D] Various embodiments of the claimed invention relate to an anti-IL-la
antibody for use
in reducing anxiety in a human subject that has acne.
4
Date Recue/Date Received 2021-10-15
CA2886757
General Methodology
[0017] Methods involving conventional immunological and molecular biological
techniques
are described herein. Immunological methods (for example, assays for detection
and
localization of antigen-Ab complexes, immunoprecipitation, inununoblotting,
and the like)
are generally known in the art and described in methodology treatises such as
Current
Protocols in Immunology, Coligan et al., ed., John Wiley & Sons, New York.
Techniques of
molecular biology are described in detail in treatises such as Molecular
Cloning: A
Laboratory Manual, 2nd ed., vol. 1-3, Sambrook et al., ed., Cold Spring Harbor
Laboratory
Press, Cold Spring Harbor, N.Y., 2001; and Current Protocols in Molecular
Biology, Ausubel
et al., ed., Greene Publishing and Wiley-Interscience, New York. Ab methods
are described
in Handbook of Therapeutic Abs, Dubel, S., ed., Wiley-VCH, 2007. General
methods of
medical treatment are described in McPhee and Pap adakis, Current Medical
Diagnosis and
Treatment 2010, 49th Edition, McGraw-Hill Medical, 2010; and Fauci et al.,
Harrison's
Principles of Internal Medicine, 17th Edition, McGraw-Hill Professional, 2008.
Methods in
dermatology are described in James et aL, Andrews' Diseases of the Skin:
Clinical
Dermatology - Expert Consult, 11th Ed., Saunders, 2011; and Bums et al.,
Rook's Textbook
of Dermatology, 8th Ed., Wiley-Blackwell, 2010.
Treatment
[0018] The compositions and methods described herein are useful for treating
skin
inflammation (e.g., associated with rosacea, eczema, psoriasis, xerosis,
dermatitis, acne,
pyoderma gangrenosum, urticaria, lichenoid disorders, bullous diseases such as
bullous
pemphigoid, cutaneous vasculitis, and granulomatous skin diseases) as well as
psychiatric
4a
Date ecue/Date Received 2021-01-15
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
conditions (e.g., anxiety, depression, and poor self image) in a mammalian
subject by
administering to the subject a pharmaceutical composition including an amount
of an anti-IL-
1 a Ab effective to improve at least one characteristic of the inflammation
(e.g., reduction in
the number or size of lesions, reduction of redness, and reduction in
itchiness) or psychiatric
condition in the subject. The mammalian subject might be any that suffers from
skin
inflammation or a psychiatric condition including, human beings, dogs, cats,
horses, cattle,
sheep, goats, and pigs. Human subjects might be male, female, adults,
children, seniors (65
and older), and those with other diseases. Particularly preferred subjects are
those whose
disease has progressed or failed to respond after treatment with other anti-
inflammatory or
anti-microbial agents such as retinoids, antibiotics, steroids or cytokine
inhibitors such as
TNEalpha inhibitors. Subjects who have developed a human anti-human antibody
response
due to prior administration of therapeutic antibodies are preferred when the
anti-IL-1a Ab is
a true human Ab (e.g., one that is naturally expressed in a human subject)
such as MABpl.
Any type of inflammatory skin disease susceptible to treatment with an anti-IL-
1a Ab might
be targeted. Anti-IL-1a Ab administration is thought to be particularly
effective for treating
acne vulgaris and psoriasis vulgaris.
Antibodies and other Agents that Target IL-la
[0019] Any suitable type of Ab that specifically binds IL-la and reduces a
characteristic of a
psychiatric condition, skin inflammation and/or an inflammatory skin disease
such as acne
vulgaris or psoriasis vulgaris in a subject might he used in the invention.
For example, the
anti-IL-la Ab used might be mAb, a polyclonal Ab, a mixture of mAbs, or an Ab
fragment
or engineered Ab-like molecule such as an scFv. The Ka of the Ab is preferably
at least 1
x109 M-1 or greater (e.g., greater than 9 x101 M-1, 8 xiom 104, 7 xioto N4-1,
6 x101 M-1, 5
x1010 M-1, 4 x1010 M-1, 3 x1010 M-1, 2 x1010 M-1, or 1 x1010 M-1). In a
preferred embodiment,
the invention utilizes a fully human mAb that includes (i) an antigen-binding
variable region
that exhibits very high binding affinity (e.g., at least nano or picomolar)
for human IL-la and
(ii) a constant region. The human Ab is preferably an IgG1 , although it might
be of a
different isotype such as IgM, IgA, or IgE, or subclass such as IgG2, IgG3, or
IgG4. One
example of a particularly useful mAb is MABp 1, an IL-la-specific IgG1 mAb
described in
U.S. patent application serial number 12/455,458 filed on June 1, 2009. Other
useful mAbs
are those that include at least one but preferably all the CDRs of MABpl.
[NM Because B lymphocytes which express Ig specific for human IL-la occur
naturally in
human beings, a presently preferred method for raising mAbs is to first
isolate such a B
lymphocyte from a subject and then immortalize it so that it can be
continuously replicated in
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
culture. Subjects lacking large numbers of naturally occurring B lymphocytes
which express
Ig specific for human IL-la may be immunized with one or more human IL-la
antigens to
increase the number of such B lymphocytes. Human mAbs are prepared by
immortalizing a
human Ab secreting cell (e.g., a human plasma cell). See, e.g., U.S. patent
no. 4,634,664.
[(021] In an exemplary method, one or more (e.g., 5, 10, 25, 50, 100, 1000, or
more) human
subjects are screened for the presence of such human IL-la-specific Ab in
their blood. Those
subjects that express the desired Ab can then be used as B lymphocyte donors.
In one
possible method, peripheral blood is obtained from a human donor that
possesses B
lymphocytes that express human IL-I a-specific Ab. Such B lymphocytes are then
isolated
from the blood sample, e.g., by cells sorting (e.g., fluorescence activated
cell sorting,
"FACS"; or magnetic bead cell sorting) to select B lymphocytes expressing
human IL-la-
specific Ig. These cells can then be immortalized by viral transformation
(e.g., using EBV) or
by fusion to another immortalized cell such as a human myeloma according to
known
techniques. The B lymphocytes within this population that express Ig specific
for human IL-
1 a can then be isolated by limiting dilution methods (e.g., cells in wells of
a microtiter plate
that are positive for Ig specific for human IL-la are selected and
subcultured, and the process
repeated until a desired clonal line can be isolated). See, e.g., Goding,
MAbs: Principles and
Practice, pp. 59-103, Academic Press, 1986. Those clonal cell lines that
express Ig having at
least nanomolar or picomolar binding affinities for human IL-1 a are
preferred. MAbs
secreted by these clonal cell lines can be purified from the culture medium or
a bodily fluid
(e.g., ascites) by conventional Ig purification procedures such as salt cuts,
size exclusion, ion
exchange separation, and affinity chromatography.
[0022] Although immortalized B lymphocytes might be used in in vitro cultures
to directly
produce mAbs, in certain cases it might be desirable to use heterologous
expression systems
to produce mAbs. See, e.g., the methods described in U.S. patent application
number
11/754,899. For example, the genes encoding an mAb specific for human TL-la
might be
cloned and introduced into an expression vector (e.g., a plasmid-based
expression vector) for
expression in a heterologous host cell (e.g., CHO cells, COS cells, myeloma
cells, and E. coli
cells). Because Igs include heavy (H) and light (L) chains in an H2L2
configuration, the genes
encoding each may be separately isolated and expressed in different vectors.
[0023] Although generally less preferred due to the greater likelihood that a
subject will
develop an anti-Ab response, chimeric mAbs (e.g., "humanized" mAbs), which are
antigen-
binding molecules having different portions derived from different animal
species (e.g.,
variable region of a mouse Ig fused to the constant region of a human Ig),
might be used in
6
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
the invention. Such chimeric Abs can be prepared by methods known in the art.
See, e.g.,
Morrison et al., Proc. Nat'l. Acad. Sci. USA, 81:6851, 1984; Neuberger et al.,
Nature,
312:604, 1984; Takeda et al.. Nature, 314:452, 1984. Similarly, Abs can be
humanized by
methods known in the art. For example, mAbs with a desired binding specificity
can be
humanized by various vendors or as described in U.S. Pat. Nos. 5,693,762;
5,530,101; or
5,585,089.
[0024] The mAbs described herein might be affinity matured to enhance or
otherwise alter
their binding specificity by known methods such as VH and VL domain shuffling
(Marks et
al. Rio/Technology 10:779-783, 1992), random mutagenesis of the hypervariable
regions
(HVRs) and/or framework residues (Barbas et al. Proc Nat. Acad. Sci. USA
91:3809-3813,
1994; Schier et al. Gene 169:147-155, 1995; Yelton et al. J. Immunol. 155:1994-
2004, 1995;
Jackson et al., J. Immunol. 154(7):3310-9, 1995; and Hawkins et al, J. Mol.
Biol. 226:889-
896, 1992. Amino acid sequence variants of an Ab may be prepared by
introducing
appropriate changes into the nucleotide sequence encoding the Ab. In addition,
modifications
to nucleic acid sequences encoding mAbs might be altered (e.g., without
changing the amino
acid sequence of the mAb) for enhancing production of the mAb in certain
expression
systems (e.g., intron elimination and/or codon optimization for a given
expression system).
The mAbs described herein can also be modified by conjugation to another
protein (e.g.,
another mAb) or non-protein molecule. For example, a mAb might be conjugated
to a water
soluble polymer such as polyethylene glycol or a carbon nanotube (See, e.g.,
Kam et al.,
Proc. Natl. Acad. Sci. USA 102: 11600-11605, 2005). See, U.S. patent
application number
11/754,899.
[0025] Preferably, to ensure that high titers of human IL- la -specific mAb
can be
administered to a subject with minimal adverse effects, the mAb compositions
of the
invention are at least 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
20, 25, 30, 35, 40, 45,
50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.9 or more percent by weight pure
(excluding any
excipients). The mAb compositions of the invention might include only a single
type of mAb
(i.e., one produced from a single clonal B lymphocyte line) or might include a
mixture of two
or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) different types of mAbs.
[0026] To modify or enhance their function, the human IL-1 a mAbs might be
conjugated
with another molecule such as a cytotoxin. A human IL-la specific mAb might be
conjugated with one or more cytotoxins to more effectively kill cells
expressing IL-1 a.
Cytotoxins for use in the invention can be any cytotoxic agent (e.g., molecule
that can kill a
cell after contacting the cell) that can be conjugated to a human IL-la
specific mAb.
7
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
Examples of cytotoxins include, without limitation, radionuclides (e.g., 35s,
14C, 32p, 125j,
131 90Y, Zr, 9, 201, 186 188 57 213 =
Y, 11, Re, Re, Cu,
Br, and 211At), conjugated radionuclides, and
chemotherapeutic agents. Further examples of cytotoxins include, but are not
limited to,
antimetabolites (e.g., 5-fluorouricil (5-FU), methotrexate (MTX), fludarabine,
etc.), anti-
microtubule agents (e.g., vincristine, vinblastine, colchicine, taxanes (such
as paclitaxel and
docetaxel), etc.), alkylating agents (e.g.,
cyclophasphamide, melphalan,
bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g., cisplatin (also
termed cDDP),
carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyclines (e.g.,
doxorubicin,
daunorubicin, etc.), antibiotic agents (e.g., m itomycin-C), topoisomerase
inhibitors (e.g.,
etoposide, tenoposide, and camptothecins), or other cytotoxic agents such as
ricin, diptheria
toxin (DT), Pseudomonas exotoxin (PE) A, PE40, abrin, saporin, pokeweed viral
protein,
ethidium bromide, glucocorticoid, anthrax toxin and others. See, e.g., U.S.
Pat. No.
5,932,188.
[0027] While the IL-1 a specific Abs described above are preferred for use in
the invention,
in some cases, other agents that specifically target IL-la might be used so
long as their
administration leads to improvement of a characteristic of an inflammatory
skin disease
and/or a psychiatric condition. These other agents might include vaccines that
cause the
production of anti- IL-la Abs, proteins or peptides that bind IL-1 a, and
small organic
molecules which specifically target IL-la. Those that do not specifically bind
other agents
that specifically target IL-1p are preferred.
Pharmaceutical Compositions and Methods
[0028] The anti-IL-1a Ab compositions (and other agents that specifically
target IL-1a) may
be administered to animals or humans in pharmaceutically acceptable carriers
(e.g., sterile
saline), that are selected on the basis of mode and route of administration
and standard
pharmaceutical practice. A list of pharmaceutically acceptable carriers, as
well as
pharmaceutical formulations, can be found in Remington's Pharmaceutical
Sciences, a
standard text in this field, and in USP/NF. Other substances may be added to
the
compositions and other steps taken to stabilize and/or preserve the
compositions, and/or to
facilitate their administration to a subject.
[0029] For example, the Ab compositions might be lyophilized (see Draber et
al., J.
Immunol. Methods. 181:37, 1995; and PCT/US90/01383); dissolved in a solution
including
sodium and chloride ions; dissolved in a solution including one or more
stabilizing agents
such as albumin, glucose, maltose, sucrose, sorbitol, polyethylene glycol, and
glycine;
filtered (e.g., using a 0.45 and/or 0.2 micron filter); contacted with beta-
propiolactone; and/or
8
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
dissolved in a solution including a microbicide (e.g., a detergent, an organic
solvent, and a
mixture of a detergent and organic solvent.
[0030] The Ab compositions may be administered to animals or humans by any
suitable
technique. Typically, such administration will be parenteral (e.g.,
intravenous, subcutaneous,
intramuscular, or intraperitoneal introduction). The compositions may also be
administered
directly to the target site (e.g., the skin) by, for example, topical
application. Other methods
of delivery, e.g., liposomal delivery or diffusion from a device impregnated
with the
composition, are known in the art. The composition may be administered in a
single bolus,
multiple injections, or by continuous infusion (e.g., intravenously or by
peritoneal dialysis).
[0031] A therapeutically effective amount is an amount which is capable of
producing a
medically desirable result in a treated animal or human. An effective amount
of anti-IL-1 a
Ab compositions is an amount which shows clinical efficacy in patients as
measured by the
improvement in one or more symptoms of skin inflammation. As is well known in
the
medical arts, dosage for any one animal or human depends on many factors,
including the
subject's size, body surface area, age, the particular composition to be
administered, sex, time
and route of administration, general health, and other drugs being
administered concurrently.
Preferred doses range from about 0.1 to 5 (e.g., 0.05, 0.1, 0.15, 0.2, 0.3,
0.4, 0.5, 1, 2, 3, 4, 5,
or 6) mg/kg body weight. In some cases a single dose is effective at resolving
an episode of
skin inflammation. In other cases, doses may be given repeatedly, e.g., semi-
weekly, weekly,
hi-weekly, tri-weekly, semi-monthly, once every three weeks, monthly, hi-
monthly, or as
needed (if skin inflammation recurs).
EXAMPLES
[0032] Example 1 - XilonixTm
[0033] XilonixTM is a sterile injectable liquid formulation of 15 mg/mL MABp1
in a
stabilizing isotonic buffer (pH 6.4). Each 10-mi, Type I borosilicate glass
serum vial
contains 5 mL of the formulation, and is sealed with a 20-mm Daikyo Flurotec
butyl rubber
stopper and flip-off aluminum seal. The product is stored at 5 3 C, with
excursions to
room temperature permitted. The exact composition of the drug product is shown
below:
Composition of the Drug Product (Xilonixlm)
Ingredient Grade Manufacturer Concentration
MABp1 Ab CiMP XBiotech 15 mg/mL
sodium phosphate dibasic compendial JT Baker 12 mg/mL
9
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
citric acid monohydrate compendial JT Baker 2 mg/mL
Trehalose.2H20 (high-purity low compendia' Ferro- 60
mg/mL
endotoxin) Pfanstiehl
polysorbate 80 compendia' JT Baker 0.2 mg/mL
Phosphoric acid, to adjust pH compendial JT Baker 0.04
mg/mL
water for injection compendia' Microbix q.s.
Method of Administration:
[0034] The calculated volume is withdrawn from the drug (mAb)-containing
vial(s) using a
suitable syringe. The drug is then injected into a subject subcutaneously.
[0035] Example 2- Treatment of Acne Vulgaris.
[0036] An 18-year-old male presented with moderate-to-severe acne vulgaris
affecting his
arms, back, chest and face. There was significant induration of the lesions,
particularly on
the back. The patient described this as an acute outbreak but reported ongoing
acne vulgaris
problems since 15 years of age. Topical retinoids and corticosteroids had been
used in the
past with some degree of effectiveness. Also limited UV treatment, by use of
tanning beds,
had been used with limited results. The patient was given a single 3 ml
subcutaneous
injection of Xilonix (MABp1; 15mg/m1), representing a dose of 0.6 mg/kg.
[0037] The patient was observed for 2 hours post-infusion. There was no
apparent infusion
reaction, or adverse response to the drug. After 24-hours the patient was re-
evaluated.
Large lesions on the shoulder and back had dramatically reduced in size.
Reduced
inflammatory infiltration of facial lesions was evidenced by less redness of
the lesions and
reduced lesion sizes compared to pre-dose. The lesions appeared to be drying.
[0038] After 72-hours the patient was re-examined. The improvement was
remarkable.
Most lesions showed dramatically less inflammation or many were altogether non-
apparent.
Lesions on shoulder and back that had remarkable induration were resolved,
only slightly
discolored and soft to the touch. The patient's face looked essentially
normaland the patient
remarked that he was very happy with the appearance of his skin. One week
after injection
the patient showed continued improvement and all areas of skin appeared
without notable
lesions.
[0039] Example 3 ¨ Formulation of MABp1 for subcutaneous injection.
[0040] T2-18C3 is a sterile liquid formulation of 100 5 mg/mL MABp1 in a
stabilizing
isotonic formulation buffer (pII 6.4 0.1). 1.4 0.1 mL of this foimulation was
contained
within two mL Type I borosilicate glass serum vials sealed with a 20-mm Daikyo
Flurotec
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
butyl rubber stopper and flip-off aluminum seal. The product with stored
upright at 5 3 C,
with excursions to room temperature permitted. The exact composition of the
Drug Product
is shown below in Table 2:
Table 2: Composition of T2-18(73 Drug Product
'ingredient Grade lanufacturer Concentration
MABp1 antibody GMP XBiotech USA Inc 100 mg/mL
trehalose.2H20 GMP, High purity, Low endotoxin Ferro-Pfanstiehl .. 60 mg/mL
(USA)
sodium phosphate GMP, EP, USP, JP JT Baker (USA) 12 mg/mL
dibasic
citric acid monohydrate GMP, EP, USP, BP JT Baker (USA)
2 mg/mL
polysorbate 80 GMP, EP, NF, JP JT Baker (USA) none
sterile water for injection GMP, EP, USP Microbix (Canada) q.s.
[0041] Example 4- Treatment of Psoriasis.
[0042] A 48-year old male with a history of Type I psoriasis vulgaris,
diagnosed at age 5 was
treated with T2-18C3. The patient has a positive family history of psoriasis
vulgaris, with his
sibling, father, and grandmother being affected as well. He was previously
treated with
topical retinoids and vitamin D3 preparations with minimal improvement.
Previous treatment
with topical steroids and UV treatment showed benefit. Prior to administration
of T2-18C3,
the patient had no history of treatment with biologic agents.
[0043] The patient was administered 2 subcutaneous injections of MABp1 in the
lower
abdomen (a total of 160 mg MABp1) on day 0. The patient tolerated the
injections well, and
there were no complications. The patient's back was evaluated at 17 hours, 41
hours, 5 days,
6 days and 10 days post-administration. At 17 hours, a modest improvement in
the redness
associated with the lesions was observed. At 41 hours continued improvement
was noted with
a clearly observable decrease in the size and redness of the lesions. By day
5, significant
resolution of the lesions was observed. This improvement continued through day
6. The
lesions were almost completely resolved by day 10.
[0044] Example 5- Treatment of Psoriasis.
[0045] An open label trial of the True HumanTm monoclonal antibody RA-18C3
(specific for
IL-lalpha) was conducted in human subjects with moderate to severe plaque
psoriasis. Trial
subjects receive 200 mg of RA-18C3 via subcutaneous injection at Days 0, 21,
and 42 for a
total of 3 injections. PASI (Psoriasis Area and Severity Index Assessment)
scores were
obtained for each subject at different time points. All of the first five
evaluable subjects
study showed a decrease in PASI score (i.e., improvement of the disease) at
day 56. The
mean reduction in PASI scores of the first five evaluable subjects at day 56
was almost 50%.
[0046] Example 6: Interim Results of A Phase II Open Label Study of the
Safety,
11
CA2886757
Pharmacokinetics, and Efficacy of a True HumanTM Anti-Inflammatory Therapeutic
Antibody (RA-18C3) in Subjects with Moderate to Severe Acne Vulgaris.
[0047] RA-18C3 is a sterile injectable liquid formulation of MABp1 in a
stabilizing isotonic
buffer. The research population consists of subjects >18 years of age, with
moderate to
severe acne vulgaris. Subjects had an Investigator's Global Assessment of >3,
>15
inflammatory facial lesions, and were candidates for systemic therapy. 11
patients were
enrolled. Seven of the 11 enrolled subjects who had lesion count data
available for day 56
are included in the analysis. Most patients (86%) were Caucasian, median age
was 23 (19-30)
years, 5 (71%) were female. The total facial inflammatory lesion count showed
an average
improvement of 35+8% (median 34%, range 25-48%) on day 42; and 44+23% (median
42%,
range 19-71%) on day 56.
[0048] The Body Image Disturbance Questionnaire (BIDQ) is a self-administered,
clinically
validated questionnaire used to assess "negative body image". The internal
consistency,
reliability and validity of the 7-item Body Image Disturbance Questionnaire
has been
established by several prior studies, as well as its potential utility in
clinical contexts for
qualitative analysis. Recently a modified version of the BIDQ was validated
specifically for
use in patients with acne vulgaris. Self-reported measures of Modified Body
Image
Disturbance Questionnaire, collected on Day 0 (DO) and Day 21 (D21), were
analyzed. This
7-item survey tool assessed different facets of the body image construct,
including
appearance related concerns, mental preoccupation with those concerns, and
resulting
impairment of social and occupational functioning. Responding to the first
question of BIDQ
survey, all 7 subjects reported that acne is their primary skin problem and
they are concerned
about the appearance of skin. At D21, 43% showed improvement in Mental
Preoccupation
(Q2), Emotional Distress (Q3), and Social/occupational impairment (Q4); while
86% showed
stabilization with no further worsening in Interference with social life (Q5),
Interference with
school/job (Q6), and Avoidance of activities due to acne problem (Q7). The
mean score of
the six BIDQ items (Q2 to Q7) showed marked reduction at D21 from the DO
level, which
indicates an across the board improvement in the body image disturbance.
[0049] It has been hypothesized that a causal relationship exists between
underlying
inflammatory processes present in skin diseases and psychiatric medical
conditions. To
further explore this possibility, the Hospital Anxiety and Depression Scale
(HADS) was used
to assess the depression and anxiety profiles of the trial population. DO and
D21 scores were
available for all the 7 subjects. The mean anxiety score on DO and D21 were
6.1 3.1 (median
6.0) and 3.3 3.9 (median 3), respectively (A 2.9). As
observed from high DO
scores, considerable level of baseline anxiety was prevalent in the study
population (median
12
Date Recue/Date Received 2021-01-15
CA 02886757 2015-03-27
WO 2014/055541
PCMJS2013/062899
6). It is important to note that about 50% reduction (from 6.1 3.1 to 3.3 3.9)
in anxiety was
achieved by D21. The subjects showing >3 point improvement in anxiety score
had a
substantial (21% to 34%) reduction in "facial inflammatory lesion count" on
D21. Mean
depression score was 2.6 3.1 (median 1) and 2.1 3.1 (1) on DO and D21,
respectively.
Other Embodiments
[0050] It is to be understood that while the invention has been described in
conjunction with
the detailed description thereof, the foregoing description is intended to
illustrate and not
limit the scope of the invention, which is defined by the scope of the
appended claims. Other
aspects, advantages, and modifications are within the scope of the following
claims.
What is claimed is:
13
