U.S. patent application number 13/437159 was filed with the patent office on 2012-10-04 for treatment of dermatological pathologies.
This patent application is currently assigned to XBIOTECH, INC.. Invention is credited to John Simard.
Application Number | 20120251548 13/437159 |
Document ID | / |
Family ID | 46927554 |
Filed Date | 2012-10-04 |
United States Patent
Application |
20120251548 |
Kind Code |
A1 |
Simard; John |
October 4, 2012 |
Treatment of Dermatological Pathologies
Abstract
Skin inflammation in a human subject is reduced by administering
to the subject a pharmaceutical composition that includes a
pharmaceutically acceptable carrier and a therapeutically effective
amount of an agent that selectively binds IL-1.alpha..
Inventors: |
Simard; John; (Austin,
TX) |
Assignee: |
XBIOTECH, INC.
Vancouver
CA
|
Family ID: |
46927554 |
Appl. No.: |
13/437159 |
Filed: |
April 2, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61470538 |
Apr 1, 2011 |
|
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Current U.S.
Class: |
424/145.1 ;
424/158.1 |
Current CPC
Class: |
C07K 2317/21 20130101;
A61K 2039/545 20130101; A61P 17/00 20180101; C07K 16/245 20130101;
C07K 2317/76 20130101; A61P 29/00 20180101; A61K 2039/54 20130101;
A61K 2039/505 20130101; C07K 16/244 20130101 |
Class at
Publication: |
424/145.1 ;
424/158.1 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61P 17/06 20060101 A61P017/06; A61P 17/10 20060101
A61P017/10; A61P 17/00 20060101 A61P017/00; A61P 29/00 20060101
A61P029/00 |
Claims
1. A method of reducing skin inflammation in a human subject, the
method comprising the step of administering to the subject a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and an amount of an agent that selectively binds
IL-1.alpha. effective to reduce skin inflammation in the
subject.
2. The method of claim 1, wherein the agent is an anti-IL-1.alpha.
antibody.
3. The method of claim 2, wherein the anti-IL-1.alpha. antibody is
a monoclonal antibody.
4. The method of claim 3, wherein the monoclonal antibody is an
IgG1.
5. The method of claim 3, wherein the monoclonal antibody comprises
a complementarity determining region of MABp1.
6. The method of claim 3, wherein the monoclonal antibody is
MABp1.
7. The method of claim 1, wherein the skin inflammation is
associated with acne vulgaris.
8. The method of claim 1, wherein the skin inflammation is
associated with psoriasis vulgaris.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional
patent application No. 61/470,538 filed on Apr. 1, 2011.
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-1.alpha. (IL-1 60 ) to reduce skin inflammation and to
treat inflammatory skin diseases including psoriasis vulgaris and
acne vulgaris.
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.alpha. is useful for reducing skin
inflammation as well as treating inflammatory skin diseases
including psoriasis vulgaris and acne vulgaris. This discovery was
surprising for a number of reasons including previous reports that
IL-1.alpha. levels are reduced in psoriatic skin (e.g., Bonifati et
al., J Biol Regul Homeost Agents. 1997 Oct-Dec; 11(4):133-6) and a
report implicating anakinra (IL-1 receptor antagonist) as a
causative agent in the development of psoriasis (Gonzalez-Lopez et
al., British Journal of Dermatology, 158:1146-1148, 2008).
[0006] Accordingly, the invention features a method of reducing
skin inflammation in a human subject. This method 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-1.alpha. effective to reduce skin
inflammation in the subject. The agent can be an anti-IL-1.alpha.
antibody such as a monoclonal antibody (e.g., of the IgG1 isotype),
a monoclonal antibody that includes a complementarity determining
region of MABp1, or MABp1. The skin inflammation can be associated
with acne vulgaris and/or psoriasis vulgaris.
[0007] For example, one 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
pharmaceutically acceptable carrier and an amount of an
anti-IL-1.alpha. Ab (or other agent that specifically and/or
selectively binds IL-1.alpha.) effective to reduce a symptom of
skin inflammation (e.g., redness, swelling, leukocyte infiltration,
or lesion development) 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 dermatological test. The
anti-IL-1.alpha. Ab can be a mAb such as an IgG1. The
anti-IL-1.alpha. Ab can be the mAb designated as MABp1 or a mAb
that includes one or more complementarity determining regions
(CDRs) of MABp1. The skin inflammation can be associated with acne
or psoriasis. The pharmaceutical composition can be 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-1.alpha. to treat skin inflammation in
the subject and a pharmaceutical composition for treating skin
inflammation in the subject, the composition comprising an agent
that selectively binds IL-1.alpha.. In the foregoing, the agent can
be an anti-IL-1.alpha. antibody such as a monoclonal antibody
(e.g., of the IgG1 isotype), a monoclonal antibody that includes a
complementarity determining region of MABp1, or MABp1; and the skin
inflammation can be associated with acne vulgaris and/or psoriasis
vulgaris.
[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.sup.th 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').sub.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 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 Ig. A "non-Fab portion" is that
portion of an Ab not within the Fab portion, e.g., an "Fc portion"
or "Fc 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 Fc
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 HPLC 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 K.sub.d greater than about 10.sup.5,
10.sup.6, 10.sup.7, 10.sup.8, 10.sup.9, 10.sup.10, 10.sup.11, or
10.sup.12 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-1alpha specifically binds an epitope on
IL-1alpha but does not specifically bind IL-1beta (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).
[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. All applications and publications mentioned herein are
incorporated by reference in their entirety. 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 skin 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.
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, immunoblotting, 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 Papadakis, Current Medical Diagnosis and Treatment
2010, 49.sup.th Edition, McGraw-Hill Medical, 2010; and Fauci et
al., Harrison's Principles of Internal Medicine, 17.sup.th Edition,
McGraw-Hill Professional, 2008. Methods in dermatology are
described in James et al., Andrews' Diseases of the Skin: Clinical
Dermatology--Expert Consult, 11.sup.th Ed., Saunders, 2011; and
Burns et al., Rook's Textbook of Dermatology, 8.sup.th Ed.,
Wiley-Blackwell, 2010.
Treatment of Skin Inflammation
[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)
in a mammalian subject by administering to the subject a
pharmaceutical composition including an amount of an
anti-IL-1.alpha. Ab effective to improve at least one
characteristic (e.g., reduction in the number or size of lesions,
reduction of redness, and reduction in itchiness) of the
inflammation in the subject. The mammalian subject might be any
that suffers from skin inflammation 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 TNFalpha inhibitors. Subjects who have developed a human
anti-human antibody response due to prior administration of
therapeutic antibodies are preferred when the anti-IL-1.alpha. Ab
is a true human Ab (e.g., one that is naturally expressed in a
human subject) such as MABp1. Any type of inflammatory skin disease
susceptible to treatment with an anti-IL-1.alpha. Ab might be
targeted. Anti-IL-1.alpha. Ab administration is thought to be
particularly effective for treating acne vulgaris and psoriasis
vulgaris.
Antibodies and other Agents that Target IL-1.alpha.
[0019] Any suitable type of Ab that specifically binds IL-1.alpha.
and reduces a characteristic of skin inflammation and/or an
inflammatory skin disease such as acne vulgaris or psoriasis
vulgaris in a subject might be used in the invention. For example,
the anti-IL-1.alpha. 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.times.10.sup.9 M.sup.-1 or greater (e.g., greater than
9.times.10.sup.1 M.sup.-1, 8.times.10.sup.10 M.sup.-1,
7.times.10.sup.10 M.sup.-1, 6.times.10 .sup.10 M.sup.-1,
5.times.10.sup.10 M.sup.-1, 4.times.10.sup.10 M.sup.-1,
3.times.10.sup.10 M.sup.-1, 2.times.10.sup.10 M.sup.-1, or
1.times.10.sup.10 M.sup.-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-1.alpha.
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 MABp1, an IL-1.alpha.-specific IgG1 mAb
described in U.S. patent application serial number 12/455,458 filed
on Jun. 1, 2009. Other useful mAbs are those that include at least
one but preferably all the CDRs of MABp1.
[0020] Because B lymphocytes which express Ig specific for human
IL-1.alpha. 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 culture. Subjects lacking large numbers
of naturally occurring B lymphocytes which express Ig specific for
human IL-1.alpha. may be immunized with one or more human
IL-1.alpha. 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. Pat. No.
4,634,664.
[0021] 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-1.alpha.-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-1.alpha.-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-1.alpha.-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.alpha. 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-1.alpha. 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.alpha. 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
Ser. No. 11/754,899. For example, the genes encoding an mAb
specific for human IL-1.alpha. 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 H.sub.2L.sub.2 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 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.
Bio/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-1.alpha.-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.alpha.
mAbs might be conjugated with another molecule such as a cytotoxin.
A human IL-1.alpha. specific mAb might be conjugated with one or
more cytotoxins to more effectively kill cells expressing
IL-1.alpha.. 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-1.alpha.
specific mAb. Examples of cytotoxins include, without limitation,
radionuclides (e.g., .sup.35S, .sup.14C, .sup.32P, .sup.125I,
.sup.131I, .sup.90Y, .sup.89Zr, .sup.201Tl, .sup.186Re, .sup.188Re,
.sup.57Cu, .sup.213Bi, and .sup.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., mitomycin-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.alpha. specific Abs described above are
preferred for use in the invention, in some cases, other agents
that specifically target IL-1.alpha. might be used so long as their
administration leads to improvement of a characteristic of an
inflammatory skin disease. These other agents might include
vaccines that cause the production of anti- IL-1.alpha.Abs,
proteins or peptides that bind IL-1.alpha., and small organic
molecules which specifically target IL-1.alpha.. Those that do not
specifically bind other agents that specifically target IL-1.beta.
are preferred.
Pharmaceutical Compositions and Methods
[0028] The anti-IL-1.alpha. Ab compositions (and other agents that
specifically target IL-1.alpha.) 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 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.alpha. 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, bi-weekly, tri-weekly, semi-monthly, once
every three weeks, monthly, bi-monthly, or as needed (if skin
inflammation recurs).
EXAMPLES
Example 1
Xilonix.TM.
[0032] Xilonix.TM. is a sterile injectable liquid formulation of 15
mg/mL MABp1 in a stabilizing isotonic buffer (pH 6.4). Each 10-mL
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.degree. C., with excursions to room temperature permitted.
The exact composition of the drug product is shown below:
TABLE-US-00001 Composition of the Drug Product (Xilonix .TM.)
Ingredient Grade Manufacturer Concentration MABp1 Ab GMP XBiotech
15 mg/mL sodium phosphate dibasic compendial JT Baker 12 mg/mL
citric acid monohydrate compendial JT Baker 2 mg/mL
Trehalose.cndot.2H2O compendial Ferro- 60 mg/mL (high-purity low
Pfanstiehl endotoxin) polysorbate 80 compendial JT Baker 0.2 mg/mL
Phosphoric acid, to compendial JT Baker 0.04 mg/mL adjust pH water
for injection compendial Microbix q.s.
Method of Administration:
[0033] 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.
Example 2
Treatment of Acne Vulgaris
[0034] 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.TM. (MABp1;
15mg/ml), representing a dose of 0.6 mg/kg.
[0035] 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.
[0036] 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.
Example 3
Formulation of MABp1 for Subcutaneous Injection
[0037] T2-18C3 is a sterile liquid formulation of 100.+-.5 mg/mL
MABp1 in a stabilizing isotonic formulation buffer (pH 6.4.+-.0.1).
1.4.+-.0.1 mL of this formulation was contained within two mL Type
I borosilicate glass serum vials sealed with a 20-mm Daikyo
Flurotec butyl rubber stopper and flip-off aluminum seal. The
product with stored upright at 5.+-.3.degree. C., with excursions
to room temperature permitted. The exact composition of the Drug
Product is shown below in Table 2:
TABLE-US-00002 TABLE 2 Composition of T2-18C3 Drug Product Concen-
Ingredient Grade Manufacturer tration MABp1 antibody GMP XBiotech
USA 100 mg/mL Inc trehalose.cndot.2H2O GMP, High purity,
Ferro-Pfanstiehl 60 mg/mL Low endotoxin (USA) sodium phosphate GMP,
EP, USP, JP JT Baker (USA) 12 mg/mL dibasic citric acid GMP, EP,
USP, BP JT Baker (USA) 2 mg/mL monohydrate polysorbate GMP, EP, NF,
JP JT Baker (USA) none 80 sterile water GMP, EP, USP Microbix q.s.
for injection (Canada)
Example 4
Treatment of Psoriasis
[0038] 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.
[0039] 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.
Example 5
Treatment of Psoriasis
[0040] An open label trial of the True Human.TM. monoclonal
antibody RA-18C3 (specific for IL-1alpha) 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%.
Other Embodiments
[0041] 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.
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