HK1187260A - Treatment for dermatological pathologies - Google Patents

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-lα αα.

Description

Treatment of dermatological conditions

Cross Reference to Related Applications

This application claims priority to U.S. provisional patent application No. 61/470,538, filed on 1/4/2011.

Statement regarding federally sponsored research

Not applicable.

Technical Field

The present invention relates generally to the fields of medicine, dermatology, and immunology. More particularly, the invention relates to the use of antibodies (Ab) that specifically bind interleukin-1 alpha (IL-1 alpha) to reduce skin inflammation and treat inflammatory skin diseases, including psoriasis vulgaris and acne vulgaris.

Background

Inflammatory skin disorders acne, rosacea, and psoriasis afflict millions of people. These conditions, while generally not fatal, can cause physical discomfort and affect emotional well-being. There are a number of different treatments currently available for inflammatory skin disorders, including corticosteroids, vitamin D analogs, coal tar, ultraviolet light, retinoids, methotrexate, cyclosporine, hydroxyurea, antibiotics, and biologic agents such as TNF α inhibitors. While these therapies have proven useful for many patients, many cause undesirable side effects and none are ideal for every situation.

SUMMARY

The present invention is based on the discovery that: mabs that specifically bind IL-1 α are useful for reducing skin inflammation, as well as treating inflammatory skin diseases, including psoriasis vulgaris and acne vulgaris. This finding is surprising for a number of reasons, including previous reports of reduced IL-1 α levels in psoriatic skin (e.g., Bonifatti et al, J Biol Regul Homeostats, 10-12 months 1997; 11(4): 133-6), and reports suggesting that anakinra (IL-1 receptor antagonist) is a causative agent in the development of psoriasis (Gonzalez-Lopez et al, British journal of Dermatology (British journal of Dermatology), 158: 1146-.

Accordingly, the invention features a method of reducing skin inflammation in a human subject. The method can include the step of administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an agent that selectively binds IL-1 α in an amount effective to reduce inflammation of the skin of the subject. The agent can be an anti-IL-1 a antibody, such as a monoclonal antibody (e.g., of the IgG1 isotype), a monoclonal antibody comprising a complementarity determining region of mab p1, or mab p 1. The skin inflammation may be associated with acne vulgaris and/or psoriasis vulgaris.

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 that includes a pharmaceutically acceptable carrier and an anti-IL-1 α Ab (or other agent that specifically and/or selectively binds IL-1 α) in an amount 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 α Ab may be a mAb, such as an IgG 1. The anti-IL-1 α Ab may be a mAb designated mAb 1 or a mAb comprising one or more Complementarity Determining Regions (CDRs) of mAb 1. Skin inflammation may be associated with acne or psoriasis. The pharmaceutical composition may be administered to the subject by subcutaneous, intravenous, intramuscular or intradermal injection. In this 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.

In other aspects, the invention includes the use of an agent that selectively binds IL-1 α to treat skin inflammation in a subject and a pharmaceutical composition for treating skin inflammation in a subject, the composition comprising an agent that selectively binds IL-1 α. In the above, the agent may be an anti-IL-1 α antibody, such as a monoclonal antibody (e.g., of the IgG1 isotype), a monoclonal antibody comprising a complementarity determining region of mab p1, or mab p 1; and the skin inflammation may be associated with acne vulgaris and/or psoriasis vulgaris.

Unless defined otherwise, 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. The commonly understood definition of biological terms can be found in Riger (Rieger), et al, Classical Molecular Genetics Glossary (Glossary of Genetics: Classical and Molecular), 5 th edition, Schmaller Press: new York (Springer-Verlag: New York), 1991; and lewen (Lewin), jen.v (genes v), oxford university press: new York (Oxford University Press: New York), 1994. A commonly understood definition of Medical terms can be found in Stedman's Medical Dictionary, 27 th edition, Lepidote (Lippincott), Williams and Wilkins Press (Williams & Wilkins), 2000.

As used herein, an "antibody" or "Ab" is an immunoglobulin (Ig), a solution of the same or a heterologous Ig, or a mixture with multiple igs. An "Ab" may also refer to fragments and engineered forms of Ig, such as Fab, Fab 'and F (Ab')₂A fragment; and scFv's, heteroconjugate Ab, and use of Ig-derived CDRs to confer antigen specificitySex similar artificial molecules. A "monoclonal antibody" or "mAb" is an Ab expressed by a clonal B cell line, or a population of Ab molecules of a species that contains only antigen binding sites that are immunoreactive with particular epitopes of a particular antigen. A "polyclonal Ab" is a mixture of heterologous abs. Typically, a polyclonal Ab will include a plurality of different Ab molecules that bind to a particular antigen, wherein at least some of the different abs immunoreact with different epitopes of the antigen. As used herein, a polyclonal Ab may be a mixture of two or more mabs.

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., the three-dimensional pocket(s) typically formed by the CDRs of the heavy and light chains of the Ab). The "Fab portion" or "Fab region" is a papain-digested proteolytic fragment of an Ig that contains the antigen-binding portion of the Ig. A "non-Fab portion" is an Ab portion that is not within the Fab portion, such as an "Fc portion" or "Fc region". The "constant region" of an Ab is the portion of the Ab outside the variable region. Generally encompassed within the constant region is an "effector portion" of the Ab, which is the portion of the Ab that is responsible for binding other immune system components that promote an immune response. Thus, for example, a site on an Ab that binds a complement component or Fc receptor (not via the antigen binding portion) is an effector portion of the Ab.

When referring to a protein molecule such as an Ab, "purified" refers to separation from components that naturally accompany such a molecule. 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 of the non-Ab protein or other naturally occurring organic molecule with which it is naturally associated. Purity can be measured by any suitable method, such as 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 the protein naturally occurs) is "purified".

"bind" or "react with" means that a molecule recognizes and adheres to a specific second molecule in a sample, but does not substantially recognize or adhere to other molecules in the sample. Typically, an Ab that "specifically binds" another molecule has greater than about 10 to that other molecule⁵、10⁶、10⁷、10⁸、10⁹、10¹⁰、10¹¹Or 10¹²Liter/mole of K_d. 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 that selectively binds IL-1 α specifically binds to an epitope on IL-1 α, but does not specifically bind to IL-1 β (which does not have the epitope).

A "therapeutically effective amount" is an amount that produces a medically desirable effect (e.g., amelioration or prevention of a disease or a symptom of a disease) in the treated animal or human.

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 hereby incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the specific embodiments discussed below are merely illustrative and are not intended to be limiting.

Detailed Description

The present invention encompasses compositions and methods for reducing skin inflammation in a subject, including ameliorating one or more symptoms of a dermatological condition. The preferred embodiments described below illustrate adaptations of these compositions and methods. Nonetheless, in accordance with the description of these embodiments, other aspects of the invention may be made and/or practiced based on the description provided below.

General procedure

Methods involving conventional immunological and molecular biological techniques are described herein. Immunological methods (e.g., assays for detection and localization of antigen Ab complexes, immunoprecipitation, immunoblotting, etc.) are generally known in the art and are described in the methodological monograph, e.g., Current Protocols in Immunology, Countergol (Coligan), et al, ed., John Wiley & Sons, N.Y.. Molecular biology techniques are described in detail in the following monographs, such as "molecular cloning: a Laboratory Manual, 2 nd edition, Vol.1-3, ed.A. Sambruk (Sambrook), et al, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 2001; and Current protocols Molecular Biology, Austebel (Ausubel) et al, Green Publishing and Wiley-Interscience, New York. Ab methods are described in the Handbook of Therapeutic Ab (Handbook of Therapeutic Abs), Dubel S (Dubel, S.), Wiley-VCH Press (Wiley-VCH), 2007. General methods of Medical Treatment are described in macphere (mcphie) and papazakis (Papadakis), contemporary Medical Diagnosis and Treatment 2010, 49 th edition, McGraw-Hill Medical press (McGraw-Hill Medical), 2010; and Fuxi (Fauci) et al, Harrison's Principles of Internal Medicine, 17 th edition, McGraw-Hill Professional Press, 2008. Dermatological methods are described in James (James) et al, anderlus skin disease: clinical dermatologists consultation (Andrews' Diseases of the Skin: Clinical Dermatology-Expert Consult), 11 th edition, Morse (Saunders), 2011; and Pengs (Burns) et al, Rook's Textbook of Dermatology, 8 th edition, Wiley-Blackwell, 2010.

Treatment of skin inflammation

The compositions and methods described herein are useful for treating skin inflammation in a mammalian subject, e.g., associated with rosacea, eczema, psoriasis, xerosis, dermatitis, acne, pyoderma gangrenosum, urticaria, licheniform disorders, bullous diseases such as bullous pemphigoid, cutaneous vasculitis, and granulomatous skin diseases, by administering to the subject a pharmaceutical composition comprising an anti-IL-1 α Ab in an amount effective to improve at least one characteristic of inflammation (e.g., reduce the number or size of lesions, reduce redness, and reduce itching) in the subject. The mammalian subject may be any subject suffering from skin inflammation, including humans, dogs, cats, horses, cows, sheep, goats, and pigs. Human subjects can be male, female, adult, child, elderly (65 years old or older), and those suffering from other diseases. Particularly preferred subjects are those for which the disease has progressed or is unresponsive to treatment with other anti-inflammatory or antimicrobial agents, such as retinoids, antibiotics, steroids, or cytokine inhibitors, such as TNF α inhibitors. When the anti-IL-1 α Ab is a true human Ab (e.g., an Ab naturally expressed in a human subject), such as mab p1, a subject who has developed a human anti-human antibody response due to prior administration of a therapeutic antibody is preferred. Any type of inflammatory skin disease that is susceptible to treatment with an anti-IL-1 α Ab may be targeted. anti-IL-1. alpha. Ab administration is believed to be particularly effective in treating acne vulgaris and psoriasis vulgaris.

Antibodies and other agents targeting IL-1 alpha

Any suitable type of Ab that specifically binds IL-1 α and reduces the characteristics of skin inflammation and/or inflammatory skin diseases such as acne vulgaris or psoriasis vulgaris in a subject may be used in the present invention. For example, the anti-IL-1. alpha. used may be mAb, a polyclonal Ab, a mAb with multiple speciesA mixture, or an Ab fragment or engineered Ab-like molecule such as scFv. The Ab preferably has a Ka of at least 1X 10⁹M^-1Or greater (e.g., greater than 9 x 10)¹⁰M^-1、8×10¹⁰M^-1、7×10¹⁰M^-1、6×10¹⁰M^-1、5×10¹⁰M^-1、4×10¹⁰M^-1、3×10¹⁰M^-1、2×10¹⁰M^-1Or 1X 10¹⁰M^-1). In a preferred embodiment, the invention utilizes a fully human mAb that comprises (i) an antigen-binding variable region that exhibits very high binding affinity (e.g., at least nanomolar or picomolar) for human IL-1 α and (ii) a constant region. The human Ab is preferably an IgG1, but it may also be of a different isotype, such as IgM, IgA, or IgE, or subclass such as IgG2, IgG3, or IgG 4. An example of a particularly useful mAb is mAb 1, an IL-1 α -specific IgG1 mAb described in U.S. patent application serial No. 12/455,458 filed 6/1/2009. Other useful mabs are those that include at least one but preferably all of the CDRs of the multiple CDRs of mAb p 1.

Since B lymphocytes expressing Ig specific for human IL-1 α occur naturally in humans, the presently preferred method for mAb production is: such a B lymphocyte is first isolated from a subject and then immortalized so that it can replicate continuously in culture. Subjects lacking a large number of naturally occurring B lymphocytes expressing Ig specific for human IL-1 α can be immunized with one or more human IL-1 α antigens in order 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, for example, U.S. patent No. 4,634,664.

In one 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 α -specific abs in their blood. Those subjects expressing the desired Ab can then be used as B lymphocyte donors. In one possible approach, peripheral blood is obtained from a human donor who possesses B lymphocytes expressing human IL-1 α -specific Ab. Such B lymphocytes are then isolated from the blood sample, for example by cell sorting (e.g., fluorescence activated cell sorting, "FACS"; or magnetic bead cell sorting) to select B lymphocytes expressing human IL-1 α -specific Ig. These cells are then immortalised by viral transformation (e.g. using EBV) or by fusion with another immortalised cell, such as a human myeloma cell, according to known techniques. B lymphocytes within this population expressing an Ig specific for human IL-1 α can then be isolated by limiting dilution methods (e.g., selecting and subculturing cells positive for an Ig specific for human IL-1 α in wells of a microtiter plate, and repeating this process until the desired clonal line can be isolated). See, e.g., golitin (Goding), "monoclonal antibodies: principles and Practice (MAbs: Priniplsasand Practice), pp 59-103, Academic Press, 1986. Those clonal cell lines expressing Ig having at least nanomolar or picomolar binding affinity for human IL-1 α are preferred. Mabs secreted by these clonal cell lines can be purified from culture media or body fluids (e.g., ascites fluid) by conventional Ig purification procedures such as salt rejection (salt cut), size exclusion, ion exchange separation, and affinity chromatography.

While immortalized B lymphocytes can be used in vitro culture to produce mabs directly, in some cases it may be desirable to use a heterologous expression system to produce mabs. See, for example, the method described in U.S. patent application No. 11/754,899. For example, a gene encoding a mAb specific for human IL-1 α can be cloned and introduced into an expression vector (e.g., a plasmid-based expression vector) for expression in heterologous host cells (e.g., CHO cells, COS cells, myeloma cells, and e. Since Ig comprises a heavy (H) chain and a light (L) chain (in one H)₂L₂In configuration), the genes encoding each chain can be isolated separately and expressed in different vectors.

Although generally less preferred because of the greater likelihood that a subject will develop an anti-Ab response, chimeric mabs (e.g., "humanized" mabs) that are antigen-binding molecules having different portions derived from different animal species (e.g., the variable region of a mouse Ig fused to the constant region of a human Ig) can be used in the present invention. Such chimeric abs may 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; wutian (Takeda) et al, Nature 314:452,1984. Similarly, abs may be humanized by methods known in the art. For example, the identification may be by different suppliers or as described in U.S. Pat. nos. 5,693,762; 5,530,101; or 5,585,089, humanizing the mAb with the desired binding specificity.

The mAbs described herein may 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 mutation of hypervariable regions (HVR) and/or framework residues (Barbas et al, Proc. Natl. 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: 1995; J. Immunol. 155:1994, 2004; Jackson et al, J. Immunol. J. Immunol. 889, J. Okino. J. 886, J. Biol et al, J. Immunol. 889, 1992, J. Biol et al, 889, J. Immunol. J. Immunol. 154, 1992, 226, Biol. Immunol. An amino acid sequence variant of an Ab may be prepared by introducing appropriate changes into the nucleotide sequence encoding the Ab. In addition, modifications of the nucleic acid sequence encoding the mAb (e.g., without altering the amino acid sequence of the mAb) can be altered for enhancing production of the mAb in certain expression systems (e.g., intron removal and/or codon optimization for a given expression system). The mabs described herein may also be modified by conjugation to another protein (e.g., another mAb) or a non-protein molecule. For example, a mAb can be conjugated to a water-soluble polymer (e.g., polyethylene glycol) or carbon nanotubes (see, e.g., Carm (Kam) et al, Proc. Natl. Acad. Sci. USA 102:11600-11605, 2005). See, U.S. patent application No. 11/754,899.

Preferably, to ensure that high titers of human IL-1 α -specific mabs are administered to a subject with minimal side 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 higher percent pure by weight (excluding any excipients). The mAb compositions of the invention can include only a single type of mAb (i.e., a mAb produced by a single clonal B lymphocyte cell line) or can include a mixture of two or more (e.g., 2, 3, 4, 5,6, 7, 8, 9, 10, or more) different types of mabs.

To modify or enhance their function, human IL-1 α mabs may be conjugated to another molecule (e.g., a cytotoxin). A human IL-1 α -specific mAb can be conjugated to one or more cytotoxins to more effectively kill cells expressing IL-1 α. The cytotoxin used in the present invention may be any cytotoxic agent (e.g., a molecule that can kill a cell upon contact with the cell) that can be coupled to a human IL-1 α -specific mAb. Examples of cytotoxins include, but are not limited to: a radionuclide (for example,³⁵S、¹⁴C、³²P、¹²⁵I、¹³¹I、⁹⁰Y、⁸⁹Zr、²⁰¹Tl、¹⁸⁶Re、¹⁸⁸Re、⁵⁷Cu、²¹³bi. And²¹¹at), a conjugated radionuclide, and a chemotherapeutic agent. Additional examples of cytotoxins include, but are not limited to: antimetabolites (e.g., 5-fluorouracil (5-FU), Methotrexate (MTX), fludarabine, and the like), antimicrotubule agents (e.g., vincristine, vinblastine, colchicine, taxanes)(e.g., paclitaxel and docetaxel), etc.), alkylating agents (e.g., cyclophosphamide, melphalan, dichloroethylnitrosourea (BCNU), etc.), platinum agents (e.g., cisplatin (also known as 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, teniposide, and camptothecin), or other cytotoxic agents such as ricin, Diphtheria Toxin (DT), Pseudomonas Exotoxin (PE) A, PE40, abrin, saporin, pokeweed viral protein, ethidium bromide, glucocorticoids, anthrax toxin, and others. See, for example, U.S. patent No. 5,932,188.

Although the above-described IL-1 α -specific abs are preferred for use in the present invention, other agents that specifically target IL-1 α may be used in some cases, so long as they are administered to cause an improvement in the characteristics of inflammatory skin diseases. These other agents may include vaccines that elicit the production of anti-IL-1 α abs, proteins or peptides that bind IL-1 α, and small organic molecules that specifically target IL-1 α. Those that do not specifically bind other agents that specifically target IL-1 β are preferred.

Pharmaceutical compositions and methods

The anti-IL-1 α Ab composition (and other agents that specifically target IL-1 α) can be administered to animals or humans in pharmaceutically acceptable carriers (e.g., sterile saline) that are selected based on the mode and route of administration and standard pharmaceutical procedures. The list of pharmaceutically acceptable carriers together with Pharmaceutical formulations can be found in Remington's Pharmaceutical Sciences, standard text in the art, and in USP/NF. Other substances may be added to these compositions and other steps taken to stabilize and/or preserve these compositions, and/or facilitate their administration to a subject.

For example, these Ab compositions can be lyophilized (see Delabell (Draber) et al, journal of immunological methods 181:37,1995; and PCT/US 90/01383); dissolving in a solution containing sodium ions and chloride ions; dissolving in a solution containing one or more stabilizers (such as albumin, glucose, maltose, sucrose, sorbitol, polyethylene glycol, and glycine); filtration (e.g., using a 0.45 μm and/or 0.2 μm filter); contacting with beta-propiolactone; and/or dissolved in a solution comprising a microbicide (e.g., a detergent, an organic solvent, and a mixture of a detergent and an organic solvent).

The Ab composition can be administered to an animal or human by any suitable technique. Typically, such administration will be parenteral (e.g., intravenous, subcutaneous, intramuscular, or intraperitoneal introduction). These compositions can also be administered directly to a target site (e.g., skin) by, for example, topical application. Other delivery methods, such as liposome delivery or diffusion from a device impregnated with the composition, are known in the art. The composition may be administered as a single bolus, multiple injections, or by continuous infusion (e.g., intravenously or by peritoneal dialysis).

A therapeutically effective amount is an amount that produces a medically desirable result in the treated animal or human. An effective amount of an anti-IL-1 α Ab composition is an amount that shows clinical efficacy in a patient as measured by improvement of one or more symptoms of skin inflammation. As is well known in the medical arts, the 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 dosages 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 to address the skin inflammatory event. In other cases, the dose may be administered repeatedly, for example, once every half week, once every two weeks, once every three weeks, once every half month, once every three weeks, once every month, once every two months, or as needed (if skin inflammation recurs).

Examples of the invention

Example 1 Xilonix^TM

Xilonix^TMIs a sterile injectable liquid formulation of MABp1 at 15mg/mL in a stable isotonic buffer (pH 6.4). Each 10mL type I borosilicate glass serum bottle contained 5mL of the formulation and was sealed with a 20mm Daikyo Flurotec butyl rubber stopper and flip aluminum seal. The product was stored at 5 ℃. + -. 3 ℃ and allowed to drift to room temperature. The exact composition of the drug is as follows:

the administration method comprises the following steps:

the calculated volume is withdrawn from one or more vials containing the drug (mAb) using a suitable syringe. The drug is then injected subcutaneously into the subject.

Example 2-treatment of acne vulgaris.

An 18 year old male presented with moderate to severe acne vulgaris affecting his arms, back, chest and face. There is significant stiffening of the lesion particularly on the back. The patient reported that this was an acute outbreak, but reported that acne vulgaris was a problem since the age of 15. Topical retinoids and corticosteroids have been used in the past and are somewhat effective. There is also limited success with limited UV treatment by using a tanning bed. The patient was given a single 3ml bolus of Xilonix^TM(MABpl; 15 mg/ml) (representing a dose of 0.6 mg/kg) were injected subcutaneously.

The patient was observed for 2 hours after infusion. Has no obvious infusion reaction or adverse reaction to the medicine. The patients were again evaluated 24 hours later. The size of large lesions on the shoulder and back is significantly reduced. A reduction in redness and reduction in lesion size of the lesion compared to before administration confirms a reduction in inflammatory infiltration of the facial lesion. These lesions appear to dry out.

The patient was again examined after 72 hours. The improvement was significant. Most lesions show significantly reduced inflammation or many are not evident at all. The lesions that were significantly hardened on the shoulders and back resolved, were only slightly colored and soft to the touch. The patient's face appears substantially normal and the patient talks about: he was very satisfied with the appearance of his skin. One week after injection, the patient showed sustained improvement and no obvious lesions were evident in all skin areas.

Example 3-mab 1 formulation for subcutaneous injection.

T2-18C3 is a sterile liquid formulation of 100 + -5 mg/mL MABp1 in a stable isotonic formulation buffer (pH 6.4 + -0.1). 1.4. + -. 0.1mL of this formulation was contained in a 2mL type I borosilicate glass serum bottle sealed with a 20mm Daikyo Flurotec butyl rubber stopper and inverted aluminum seal. The product was stored upright at 5 ℃. + -. 3 ℃ and allowed to drift to room temperature. The exact composition of the drug is shown in table 2 below:

example 4-treatment of psoriasis.

A48 year old male with a history of type I psoriasis vulgaris (diagnosed at 5 years) was treated with T2-18C 3. The patient had a positive family history of psoriasis vulgaris, with his brother sister, father and grandmother also affected. The patient was previously treated with a topical retinoid and vitamin D3 formulation with little improvement. Previous treatments with topical steroids and UV treatment have shown benefit. The patient had no history of treatment with a biologic prior to administration of T2-18C 3.

Patients were given 2 subcutaneous injections of MABp1 in the lower abdomen on day 0 (160 mg MABp1 total). The patient tolerated the injection well and there were no complications. The patient's back was evaluated 17 hours, 41 hours, 5 days, 6 days and 10 days after administration. At 17 hours, a modest improvement in redness associated with the lesion was observed. A sustained improvement was noted at 41 hours, and a reduction in lesion size and redness was clearly observed. By day 5, significant regression of the lesions was observed. This improvement continued until day 6. By day 10, the lesions regressed almost completely.

Example 5-treatment of psoriasis.

TrueHuman in human subjects with moderate to severe plaque psoriasis^TMOpen-ended assay for monoclonal antibody RA-18C3 (specific for IL-1. alpha.). Test subjects received 200mg of RA-18C3 via subcutaneous injection on 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 the first five evaluable subject studies on day 56 showed a decrease in PASI score (i.e., disease improvement). The average reduction in PASI scores for the first five evaluable subjects on day 56 was almost 50%.

Other embodiments

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.

Claims (15)

1. Use of an agent that selectively binds IL-1 α to treat skin inflammation in a subject.

2. The use of claim 1, wherein the agent is an anti-IL-1 α antibody.

3. The use of claim 2, wherein the anti-IL-1 α antibody is a monoclonal antibody.

4. The use of claim 3, wherein the monoclonal antibody is an IgG 1.

5. The use of claim 3, wherein the monoclonal antibody comprises a complementarity determining region of MABp 1.

6. The use of claim 3, wherein the monoclonal antibody is MABp 1.

7. The use of claim 1, wherein the skin inflammation is associated with acne vulgaris.

8. The use of claim 1, wherein the skin inflammation is associated with psoriasis vulgaris.

9. A pharmaceutical composition for treating skin inflammation in a subject, the composition comprising an agent that selectively binds IL-1 α.

10. The pharmaceutical composition of claim 9, wherein the agent is an anti-IL-1 a antibody.

11. The pharmaceutical composition of claim 10, wherein the anti-IL-1 α antibody is a monoclonal antibody.

12. The pharmaceutical composition of claim 11, wherein the monoclonal antibody comprises a complementarity determining region of MABp 1.

13. The pharmaceutical composition of claim 12, wherein the monoclonal antibody is MABp 1.

14. The pharmaceutical composition of claim 9, wherein the skin inflammation is associated with acne vulgaris.

15. The pharmaceutical composition of claim 9, wherein the skin inflammation is associated with psoriasis vulgaris.