U.S. patent application number 17/453894 was filed with the patent office on 2022-03-03 for treatment of psychiatric conditions.
The applicant listed for this patent is Janssen Biotech, Inc.. Invention is credited to John SIMARD.
Application Number | 20220062413 17/453894 |
Document ID | / |
Family ID | 1000005962594 |
Filed Date | 2022-03-03 |
United States Patent
Application |
20220062413 |
Kind Code |
A1 |
SIMARD; John |
March 3, 2022 |
TREATMENT OF PSYCHIATRIC CONDITIONS
Abstract
The number of acne lesions 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.. Anxiety and other psychiatric conditions are also
improved with this treatment.
Inventors: |
SIMARD; John; (Austin,
TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Biotech, Inc. |
Horsham |
PA |
US |
|
|
Family ID: |
1000005962594 |
Appl. No.: |
17/453894 |
Filed: |
November 8, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16112496 |
Aug 24, 2018 |
11191831 |
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17453894 |
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13928020 |
Jun 26, 2013 |
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16112496 |
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13644976 |
Oct 4, 2012 |
9724409 |
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13928020 |
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13437159 |
Apr 2, 2012 |
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13644976 |
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61470538 |
Apr 1, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 39/395 20130101;
A61K 2039/505 20130101; C07K 16/245 20130101; A61K 39/3955
20130101 |
International
Class: |
A61K 39/395 20060101
A61K039/395; C07K 16/24 20060101 C07K016/24 |
Claims
What is claimed is:
1. A method of treating skin inflammation in a human subject by
administering to the subject a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and an amount of
an agent that specifically binds IL-1.alpha. effective to reduce a
symptom of skin inflammation in the subject.
2. The method of claim 1, wherein the agent is that specifically
binds IL-1.alpha. 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
at least one of complementarity determining regions of MABp1.
6. The method of claim 5, wherein the monoclonal antibody comprises
all of the complementarity determining regions of MABp1.
7. The method of claim 6, wherein the monoclonal antibody is
MABp1.
8. The method of claim 3, wherein the Ka of the antibody is at
least 1.times.10.sup.9M.sup.-1.
9. The method of claim 1, wherein the pharmaceutical composition is
administered to the subject parenterally, subcutaneously,
intravenously, intramuscularly, intraperitoneally or
intradermally.
10. The method of claim 2, wherein the dose of the anti-IL-1.alpha.
antibody is about 0.1 to 5 mg/kg body weight.
11. The method of claim 2, wherein the anti-IL-1.alpha. antibody is
administered semi-weekly, weekly, bi-weekly, tri-weekly,
semi-monthly, once every three weeks, monthly or bi-monthly.
12. The method of claim 1, wherein the symptom of skin inflammation
is redness, swelling, leukocyte infiltration, lesion development,
or lesion number.
13. The method of claim 1, wherein the pharmaceutical composition
reduces the symptom by at least about 10%.
14. The method of claim 1, wherein administration of the
pharmaceutical composition reduces the number or size of lesions,
redness, and/or itchiness.
15. The method of claim 1, wherein the skin inflammation is
associated with rosacea, eczema, psoriasis, xerosis, dermatitis,
acne, pyoderma gangrenosum, urticaria, lichenoid disorders, bullous
diseases including bullous pemphigoid, cutaneous vasculitis, or
granulomatous skin diseases.
16. The method of claim 1, wherein the skin inflammation is
associated with pyoderma gangrenosum.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 16/112,496 filed on Aug. 24, 2018,
which is a continuation application of U.S. patent application Ser.
No. 13/928,020 filed on Jun. 26, 2013, which is a division of U.S.
patent application Ser. No. 13/644,976 filed on Oct. 4, 2012 (now
U.S. Pat. No. 9,724,409), which is a continuation-in-part
application of U.S. patent application Ser. No. 13/437,159 filed on
Apr. 2, 2012 (now abandoned), which 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-la (IL-la) 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.alpha. 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-1.alpha. 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-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.
[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
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,
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 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 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 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-la. In the foregoing, the agent can be an anti-IL-1.alpha.
antibody such as a monoclonal antibody (e.g., of the IgG1 isotype),
or a monoclonal antibody that includes a CDR of MABp1, or
MABp1.
[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, 49th 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
[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 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.alpha. 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 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 a psychiatric condition, 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.9M.sup.-1 or greater (e.g., greater than
9.times.10.sup.10M.sup.-1, 8.times.10.sup.10M.sup.-1,
7.times.10.sup.10M.sup.-16.times.10M.sup.-1,
5.times.10.sup.10M.sup.-1, 4.times.10.sup.10M.sup.-1,
3.times.10.sup.10M.sup.-1, 2.times.10.sup.10M.sup.-1, or
1.times.10.sup.10M.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 Ser. No. 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- la 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 Ser. No. 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.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 and/or a psychiatric condition. 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-1a 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.2H2O
compendial Ferro- 60 mg/mL (high-purity low endotoxin) Pfanstiehl
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;
15 mg/m1), 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
Ingredient Grade Manufacturer Concentration MABp1 antibody GMP
XBiotech USA 100 mg/mL Inc trehalose.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 80 GMP, EP,
NF, JP JT Baker (USA) none sterile water for GMP, EP, USP Microbix
q.s. 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%.
Example 6
[0041] Interim Results of A Phase II Open Label Study of the
Safety, Pharmacokinetics, and Efficacy of a True Human.TM.
Anti-Inflammatory Therapeutic Antibody (RA-18C3) in Subjects with
Moderate to Severe Acne Vulgaris.
[0042] RA-18C3 is a sterile injectable liquid formulation of MABp1
in a stabilizing isotonic buffer. The research population consists
of subjects .gtoreq.18 years of age, with moderate to severe acne
vulgaris. Subjects had an Investigator's Global Assessment of
.gtoreq.3, .gtoreq.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.
[0043] 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 (D0) 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 D0 level,
which indicates an across the board improvement in the body image
disturbance.
[0044] 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. D0 and D21 scores were available for all the 7
subjects. The mean anxiety score on D0 and D21 were 6.1.+-.3.1
(median 6.0) and 3.3.+-.3.9 (median 3), respectively (.DELTA. 2.9).
As observed from high DO scores, considerable level of baseline
anxiety was prevalent in the study population (median 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
.gtoreq.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 D0 and D21, respectively.
Other Embodiments
[0045] 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.
* * * * *