JP6750941B2 - Treatment of mental disorders - Google Patents

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to US Provisional Patent Application No. 61/709,741 filed October 4, 2012.

Description of research and development funded by the federal government Not applicable.

The present invention relates generally to the fields of medicine, dermatology and immunology. More specifically, the invention relates to the use of antibodies (Abs) that specifically bind interleukin-1α (IL-1α) to treat inflammatory skin disorders and psychiatric disorders.

The inflammatory skin diseases acne, rosacea and psoriasis afflict millions of people. Although not usually fatal, these symptoms can lead to physical discomfort and affect emotional stability. There are currently many different treatments for inflammatory skin diseases, including corticosteroids, vitamin D analogs, coal tar, UV light, retinoids, methotrexate, cyclosporine, hydroxyureas, antibiotics, and biological agents (TNF alpha inhibition. Agents and the like). Although these treatments have proven useful for many patients, many cause unwanted side effects and none are ideal for every situation.

The present invention is based on the discovery that mAbs that specifically bind IL-1α are useful in treating acne vulgaris and various mental disorders such as anxiety and bad self-image.

Accordingly, the present invention relates to methods of reducing the number of acne lesions in a human subject and methods of treating a mental disorder (eg, anxiety, depression or bad self-image) in a human subject. These methods provide a subject with a pharmaceutically acceptable carrier and an agent that selectively binds IL-1α in an amount effective to reduce the number of acne lesions or ameliorate a mental disorder in the subject. May comprise the step of administering a pharmaceutical composition comprising The agent may be an anti-IL-1α antibody (such as a monoclonal antibody (eg of the IgG1 isotype), a monoclonal antibody comprising the complementarity determining region of MABp1, or MABp1 etc.).

Another aspect of the present invention is a method of alleviating skin inflammation in a human subject, the method comprising subjecting the subject with a pharmaceutically acceptable carrier and skin inflammation (eg, redness, swelling, leukocyte infiltration, lesion development, or Administering a pharmaceutical composition comprising an amount of anti-IL-1α Ab (or other agent that specifically and/or selectively binds IL-1α) effective to alleviate the symptoms of (lesion number) By at least about 10% (eg, at least 8, 9, 10, 15, 17, 20, 30, 40, 50, 60, in a subject, as measured by any standard dermatological test). 70, 80, 90 or 100%) to reduce skin inflammation. The anti-IL-1α Ab may be a mAb (such as IgG1). The anti-IL-1α Ab may be a mAb called MABp1 or may be a mAb containing one or more complementarity determining regions (CDRs) of MABp1. The pharmaceutical composition may be administered to the subject by subcutaneous, intravenous, intramuscular, or intradermal injection. In this method, the dose may be at least 0.25 (eg, at least 0.2, 0.5, 0.75, 1, 2, 3, 4, or 5) mg/ml.

In another aspect, the present invention provides the use of an agent that selectively binds to IL-1α to treat acne and/or mental disorders in a subject, and a medicament for treating acne and/or mental disorders in a subject. A composition comprising an agent that selectively binds IL-1α. As mentioned above, the agent may be an anti-IL-1α antibody (such as a monoclonal antibody (eg of the IgG1 isotype), a monoclonal antibody comprising the CDRs of MABp1, or MABp1 etc.).

Unless otherwise defined, all terminology used herein has the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. A generally well-understood definition of biological terms can be found in Rieger et al. ^{, Glossary of Genetics: Classical and Molecular} , 5 th edition, Springer-Verlag: New York, 1991; and Lewin, Genes V, Oxford University Press : New York, can be found in 1994. Generally are well understood definitions of medical ^{terms, Stedman's Medical Dictionary, 27 th} Edition, Lippincott, can be seen in Williams & Wilkins, 2000.

As used herein, an "antibody" or "Ab" is an immunoglobulin (Ig), a homologous or heterologous Ig solution, or a mixture of Igs. “Ab” also confers antigen specificity using fragments of Ig and engineered variants (Fab, Fab′, and F(ab′) ₂ fragments; scFv, heteroconjugate Abs, and Ig-derived CDRs. Similar artificial molecule). "Monoclonal antibody" or "mAb" refers to a clonal B cell line, or a population of Ab molecules, that contains only one of the antigen binding sites capable of immunoreacting with a particular epitope of a particular antigen. It is Ab. A "polyclonal Ab" is a mixture of heterologous Abs. Typically, a polyclonal Ab will contain a myriad of different Ab molecules that bind a particular antigen, at least a portion of the different Abs being immune-responsive to different epitopes of the antigen. As used herein, a polyclonal Ab may be a mixture of 2 or more mAbs.

The "antigen-binding portion" of Ab is contained in the variable region of the Fab portion of Ab and is the portion of Ab that confers antigen specificity to Ab (ie, generally, the heavy and light chains of Ab). It is a three-dimensional pocket formed by CDR. "Fab portion" or "Fab region" is a proteolytic fragment of papain digested Ig and contains the antigen binding portion of Ig. A "non-Fab portion" is a portion of Ab that is not within the Fab portion (eg, "Fc portion" or "Fc region"). The “invariant region” of Ab is the portion of Ab outside the variable region. Usually included within the constant region is the "effector portion" of Ab, which is the portion of Ab responsible for binding to other immune system components that facilitate the immune response. Thus, for example, the site of Ab that binds the complement component (or not through the antigen-binding portion) to the Fc receptor is the effector portion of Ab.

When referring to a protein molecule such as Ab, "purified" means separated from the components that naturally accompany such molecule. Typically, an Ab or protein is purified means at least about 10% by weight (eg, 9% by weight, 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70 wt%, 80 wt%, 90 wt%, 95 wt%, 98 wt%, 99 wt%, 99.9 wt% and 100 wt%), non-Ab proteins, or other naturally occurring, naturally occurring This is the case when it is free from the associated organic molecule. Purity may be measured by any suitable method (eg, column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis). A chemically synthesized protein, or other recombinant protein produced in a cell type other than the naturally occurring cell type, is “purified”.

By “bind”, “binds”, or “reacts with” is meant that a molecule recognizes a particular second molecule in the sample and Attached to, but does not substantially recognize or attach to other molecules in the sample. Usually, an Ab that "specifically binds" another molecule has a _Kd of about 10 ⁵ , 10 ⁶ , 10 ⁷ , 10 ⁸ , 10 ⁹ , 10 ¹⁰ , 10 ¹¹ or 10 ¹² for that other molecule. Greater than liter/mole. An Ab that "selectively binds" a first molecule specifically binds to the first molecule at a first epitope but not to other molecules that do not have the first epitope. For example, an Ab that selectively binds IL-1alpha specifically binds to an epitope of IL-1alpha but not IL-1beta (which has no epitope).

A "therapeutically effective amount" is an amount capable of producing a medically desired effect in a treated animal or human (eg, amelioration or prevention of a disease or symptom of a disease).

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 case of conflict, the present specification, including definitions, will control. Also, the particular embodiments discussed below are for purposes of illustration only and are not intended to be limiting.

The present invention includes compositions and methods for alleviating skin inflammation that include ameliorating one or more symptoms of a dermatological condition in a subject. The preferred embodiments described below illustrate the adaptation of these compositions and methods. Nevertheless, 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 Methods involving conventional immunological and molecular biology techniques are described herein. Immunological methods (eg, assays for detection and localization of antigen-Ab complexes, immunoprecipitations, immunoblotting, etc.) are generally known in the art and the methodology specialized in the Current Protocols. Immunology, Coligan et al., ed., John Wiley & Sons, New York, etc.). Molecular biology technology, technical literature ^{(Molecular Cloning:... A} Laboratory Manual, 2 nd 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, etc.). The Ab method is described in Handbook of Therapeutic Abs, Dubel, S.; , Ed. , Wiley-VCH, 2007. General methods of medical treatment, McPhee and Papadakis, Current Medical Diagnosis and Treatment 2010,49 th Edition, McGraw-Hill Medical, 2010; and Fauci et al. ^{, Harrison's Principles of Internal Medicine,} 17 th Edition, are described in the McGraw-Hill Professional, 2008. Methods in dermatology are described by James et al. , Andrews' Diseases of the Skin: Clinical Dermatology-Expert Consult, 11 th Ed. , Saunders, 2011; and Burns et al. , Look's Textbook of Dermatology, 8 ^th Ed. , Wiley-Blackwell, 2010.

Treatment The compositions and methods described herein provide for skin inflammation (e.g., rosacea, eczema, psoriasis, xerosis, dermatitis, acne, necrotizing pyoderma, urticaria) of a mammalian subject. Lichenoid diseases, bullous diseases (such as bullous pemphigoid), cutaneous vasculitis and granulomatous skin diseases) and mental disorders (eg, anxiety, depression and bad self-image) can A pharmaceutical composition comprising an amount of anti-IL-1α Ab effective to ameliorate at least one property of inflammation or psychosis (eg, relief of number and size of lesions, relief of redness, and relief of pruritus). It is useful to treat by administering A mammalian subject can be anything that suffers from skin inflammation or a mental disorder and includes humans, dogs, cats, horses, cows, sheep, goats and pigs. Human subjects can be men, women, adults, children, the elderly (ages 65 and older), and people with other disorders. Particularly preferred subjects are those with advanced disease or unresponsiveness after treatment with other anti-inflammatory or antibacterial agents (such as retinoids), antibiotics, steroids, or cytokine inhibitors (such as TNF alpha inhibitors). is there. When the anti-IL-1α Ab is a genuine human Ab (eg, naturally expressed in a human subject) (MABp1 etc.), the human anti-human antibody response is attributed to prior administration of the therapeutic antibody. Developed subjects are preferred. Any type of inflammatory skin disease susceptible to treatment with anti-IL-1α Ab may be targeted. Administration of anti-IL-1α Abs is believed to be particularly effective in treating acne vulgaris and psoriasis vulgaris.

Antibodies Targeting IL-1α and Other Agents By specifically binding to IL-1α, it is possible to prevent mental disorders, skin inflammation and/or inflammatory skin diseases (such as acne vulgaris or psoriasis vulgaris) in a subject. Any type of Ab suitable for mitigating properties may be used in the present invention. For example, the anti-IL-1α Ab used may be a mAb, a polyclonal Ab, a mixture of mAbs, or an Ab fragment, or an engineered Ab-like molecule (scFv, etc.). The Ka of Ab is preferably at least 1×10 ⁹ M ⁻¹ or more (for example, 9×10 ¹⁰ M ⁻¹ , 8×10 ¹⁰ M ⁻¹ , 7×10 ¹⁰ M ⁻¹ , 6×10 ¹⁰ M ^{− 1} , 5×10 ¹⁰ M ⁻¹ , 4×10 ¹⁰ M ⁻¹ , 3×10 ¹⁰ M ⁻¹ , 2×10 ¹⁰ M ⁻¹ or more than 1×10 ¹⁰ M ⁻¹ ). In a preferred embodiment, the invention comprises (i) an antigen-binding variable region that exhibits a very high binding affinity (eg, at least nano or picomolar) for human IL-1α, and (ii) a constant region. Utilizes a fully human mAb. The human Ab is preferably IgG1. It may be of various isotypes (such as IgM, IgA or IgE) or of subclass (such as IgG2, IgG3 or IgG4). One example of a particularly useful mAb is MABp1 (IL-1α-specific IgG1 mAb) (described in US patent application Ser. No. 12/455,458 filed June 1, 2009). Other useful mAbs are those containing at least one, and preferably all, of the MABp1 CDRs.

Since B lymphocytes that express Ig specific for human IL-1α are naturally present in humans, a presently preferred method of increasing mAbs is to first isolate such B lymphocytes from a subject and then And immortalize it so that it can be continuously replicated in culture. Subjects deficient in many of the naturally occurring B lymphocytes that express Ig specific for human IL-1α are immunized with one or more human IL-1α antigens to generate such B lymphoids. The number of spheres can be increased. Human mAbs are prepared by immortalizing human Ab secreting cells (eg, human plasma cells). See, for example, U.S. Pat. No. 4,634,664.

In an exemplary method, one or more (eg, 5, 10, 25, 50, 100, 1000 or more) human subjects are assessed for the presence or absence of such human IL-1α-specific Abs in their blood. To be screened. Subsequently, a subject expressing the desired Ab may be a B lymphocyte donor. In one possible method, peripheral blood is obtained from a human donor possessing B lymphocytes expressing human IL-1α-specific Abs. Subsequently, such B lymphocytes were isolated from a blood sample, eg, by cell sorting (eg, fluorescence activated cell sorting “FACS”; or magnetic bead cell sorting), to obtain human IL-1α-specific. B lymphocytes expressing Ig are selected. These cells may then be immortalized (according to known techniques) by viral transformation (eg with EBV) or by fusion to another immortalized cell (such as human myeloma). Subsequently, B lymphocytes within this population that express Ig specific for human IL-1α are defined by limiting dilution methods (eg, microbes that are positive for Ig specific for human IL-1α, The cells in the wells of the titer plate are selected and subcultured, and the process is repeated) until the desired clonal line can be isolated) and isolated. For example, in Goding, MAbs: Principles and Practice, pp. 59-103, Academic Press, 1986. Clonal cell lines expressing at least nanomolar, or picomolar, Ig with binding affinity for human IL-1α are preferred. MAbs secreted by these clonal cell lines may be purified from culture media or body fluids (eg, ascites fluid) by conventional Ig purification procedures such as salt cutting, size exclusion, ion exchange separation, and affinity chromatography.

Immortalized B lymphocytes may be used in in vitro culture to produce mAbs directly, although in certain cases it may be desirable to use a heterologous expression system to produce mAbs. See, for example, the method described in US patent application Ser. No. 11/754,899. For example, a gene encoding a mAb specific for human IL-1α has been cloned for expression in heterologous host cells (eg, CHO cells, COS cells, myeloma cells, and E. coli cells) and expression vectors (eg, , A plasmid-based expression vector). Since Ig contains heavy (H) and light (L) chains in the H ₂ L ₂ construct, the genes encoding each should be isolated separately and expressed in different vectors.

Although less preferred, chimeric mAbs (eg, "humanized" mAbs) (various from different animal species) are generally less preferred due to the greater likelihood that the subject will develop an anti-Ab response. Antigen-binding molecules having a portion of (eg, the variable region of mouse Ig fused to the constant region of human Ig) may be used in the present invention. Such chimeric Abs may be prepared by methods known in the art. For example, 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 may be humanized by methods known in the art. For example, a mAb with the desired binding specificity can be produced by humans as described by various vendors or in US Pat. No. 5,693,762; US Pat. No. 5,530,101; or US Pat. No. 5,585,089. May be embodied.

The mAbs described herein have their binding specificities determined by known methods (VH and VL domain shuffling (Marks et al. Bio/Technology 10:779-783, 1992), hypervariable regions (HVR). ) And/or random mutagenesis of 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) to enhance or otherwise alter affinity maturation.Ab amino acid sequence variants of Ab are prepared by introducing appropriate changes into the nucleotide sequence encoding Ab. Also, modifications to the nucleic acid sequence encoding the mAb may be altered (eg, without changing the amino acid sequence of the mAb) to increase production of the mAb in certain expression systems (eg, given Intron removal and/or codon optimization for the expression system of M. A. The mAbs described herein have also been modified by conjugation to another protein (eg, another mAb) or non-protein molecule. For example, the mAb may be conjugated to a water-soluble polymer such as polyethylene glycol or carbon nanotubes (see, eg, Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605, 2005). See U.S. Patent Application No. 11/754,899.

Preferably, in order to ensure that high titers of human IL-1α-specific mAb can be administered to a subject with minimal side effects, the mAb composition of the invention comprises 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, Greater than 95, 96, 97, 98, 99, 99.9 weight percent pure (excluding any excipients). The mAb compositions of the present invention may include only a single type of mAb (ie, those produced from a single clonal B lymphocyte lineage), or more than one (eg, 2, 3, 4, 5). , 6, 7, 8, 9, 10 or more) of different types of mAbs.

The human IL-1α mAb may be conjugated to another molecule (such as a cytotoxin) to modify or enhance function. Human IL-1α-specific mAbs may be conjugated with one or more cytotoxins to kill IL-1α expressing cells more effectively. The cytotoxin used in the present invention may be any cytotoxic agent that can be conjugated to a human IL-1α-specific mAb (eg, a molecule that can kill a cell after contacting it). Examples of cytotoxins include, but are not limited to, radionuclides (eg, ³⁵ S, ¹⁴ C, ³² P, ¹²⁵ I, ¹³¹ I, ⁹⁰ Y, ⁸⁹ Zr, ²⁰¹ Tl, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁵⁷ Cu, ²¹³ Bi. , And ²¹¹ At), conjugated radionuclides, and chemotherapeutic agents. Further examples of cytotoxins include, but are not limited to, antimetabolites (eg, 5-fluorouracil (5-FU), methotrexate (MTX), fludarabine, etc.), anti-microtubule agents (eg, vincristine, vinblastine, colchicine). , Taxanes (such as paclitaxel and docetaxel), alkylating agents (such as cyclophosphamide), melphalan, bischloroethylnitrosurea (BCNU), and platinum agents (such as cisplatin (cDDP)). ), carboplatin, oxaliplatin, JM-216, CI-973 etc.), anthracycline (eg doxorubicin, daunorubicin etc.), antibiotics (eg mitomycin-C), topoisomerase inhibitors (eg etoposide, tenoposide (eg. and other cytotoxic agents (ricin, diphtheria toxin (DT), Pseudomonas exotoxin (PE) A, PE40, abrin, saporin, pokeweed virus protein, ethidium bromide, glucocorticoid, anthrax toxin, etc.) ) And the like. See, for example, US Pat. No. 5,932,188.

While the IL-1α-specific Abs described above are preferred for use in the present invention, in some cases, other agents that specifically target IL-1α may be administered by administration of inflammatory skin disorders and/or It may be used insofar as it improves the characteristics of the mental disorder. These other agents may include vaccines that result in the production of anti-IL-1α Abs, proteins or peptides that bind IL-1α, and small organic molecules that specifically target IL-1α. Those that do not specifically bind to other agents that specifically target IL-1β are preferred.

Pharmaceutical Compositions and Methods Anti-IL-1α Ab compositions (and other agents that specifically target IL-1α) are administered to animals or humans based on the mode and route of administration, and standard pharmaceutical practice. It may be administered in a pharmaceutically acceptable carrier of choice (eg sterile saline). A list of pharmaceutically acceptable carriers, and pharmaceutical formulations, can be found in Remington's Pharmaceutical Sciences (standard text in this field) and USP/NF. Other substances may be added to the composition and other steps taken to stabilize and/or preserve the composition and/or facilitate administration to a subject.

For example, the Ab composition may be lyophilized (see Draber et al., J. Immunol. Methods. 181:37, 1995; and International Application PCT/US90/01383); sodium ion and chloride. It may be dissolved in a solution containing ions; it may be dissolved in a solution containing one or more stabilizers such as albumin, glucose, maltose, sucrose, sorbitol, polyethylene glycol, and glycine. It may be filtered (e.g. using a 0.45 and/or 0.2 micron filter); contacted with beta-propiolactone; and/or a solution containing a bactericide (e.g. Detergents, organic solvents, and mixtures of detergents and organic solvents).

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

A therapeutically effective amount is an amount that can produce the medically desired results in the treated animal or human. An effective amount of anti-IL-1α Ab composition is an amount that is clinically effective in a patient and is measured by improvement in one or more signs of skin inflammation. As is well known in the medical arts, the dose for any animal or human will depend on many factors, including the size of the subject, body surface area, age, the particular composition to be administered, Gender, time and route of administration, physical condition, and other drugs that are co-administered. A preferred dose is about 0.1 to 5 (eg 0.05, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5 or 6) up to mg/kg (body weight). In some cases, a single dose is effective in restoring the manifestation of skin inflammation. In other cases, the dose may be repeated (eg, semiweekly, weekly, biweekly, thrice weekly, semimonthly, once every three weeks, monthly, bimonthly, or as needed (when skin inflammation recurs. If you do)).

Example 1-Xilonix™
Xilonix™ is a sterile injectable liquid formulation, 15 mg/mL MABp1 in stabilizing isotonic buffer (pH 6.4). Each 10-mL Type I borosilicate glass serum vial contains 5 mL of formulation and is sealed with a 20-mm Daikyo Flurotec butyl rubber stopper and flip-off aluminum seal. Store product at 5±3°C (excursion to room temperature is acceptable). The exact composition of the drug product is shown below.

Method of administration:
The calculated volume is drawn from the drug (mAb) containing vial using an appropriate syringe. Subsequently, the drug is subcutaneously injected into the subject.

Example 2-Treatment of Acne Vulgaris.
An 18-year-old man had moderate to severe acne vulgaris, extending to the arms, back, chest and face. There was significant hardening of the lesion, especially on the back. The patient described this as an acute outbreak, but reported the problem of acne vulgaris, which has been persistent since age 15. Topical retinoids and corticosteroids have been used in the past with some effect. Also, limited UV treatments have been made with tanning beds, but with limited results. Patients received a single 3 ml subcutaneous injection of Xilonix™ (MABpl; 15 mg/ml), representing a dose of 0.6 mg/kg.

The patient was observed for 2 hours after infusion. There was no apparent infusion response or adverse response to the drug. After 24 hours, the patient was reassessed. The size was dramatically reduced for large shoulder and back lesions. Reduction of inflammatory infiltrates in facial lesions was evidenced by a reduction in lesion redness and a reduction in lesion size compared to pre-dose. Lesions appeared dry.

After 72 hours, the patient was reexamined. The improvement was notable. Most lesions showed dramatically less inflammation, or much less overall. The shoulder and back lesions with significant induration were healed, only slightly discolored, and soft to the touch. The patient's face looked basically normal, and the patient stated that he was very pleased with the appearance of the skin. One week after injection, the patient showed continuous improvement and appeared to have no significant lesions on all areas of the skin.

Example 3-Formulation of MABp1 for subcutaneous injection.
T2-18C3 is a sterile liquid formulation, 100±5 mg/mL MABp1 in stabilized isotonic formulation buffer (pH 6.4±0.1). 1.4±0.1 mL of this formulation was contained in a 2 mL Type I borosilicate glass serum vial and sealed with a 20-mm Daikyo Flurotec butyl rubber stopper and a flip-off aluminum seal. Products were stored upright at 5±3°C (excursion to room temperature allowed). The exact composition of the drug product is shown in Table 2 below.

Example 4-Treatment of psoriasis.
A 48-year-old man with a history of type I psoriasis vulgaris (diagnosed as age 5) was treated with T2-18C3. The patient had a positive family history of psoriasis vulgaris, and his siblings, father and grandmother were affected as well. The patient was previously treated with topical retinoid and vitamin D3 preparations, but the improvement was modest. Previous treatment with topical steroids and UV treatment has shown benefits. Prior to administration of T2-18C3, the patient had no history of treatment with biological agents.

Patients received two subcutaneous injections of MABp1 in the lower abdomen on day 0 (160 mg total MABp1). The patient was well tolerated by injection and had no complications. The patient's back was evaluated at 17, 41, 5, 6, and 10 days post dose. At 17:00, a moderate improvement in redness associated with the lesion was observed. At 41 hours, continuous improvement was noted, with a clearly observable reduction in lesion size and redness. By day 5, significant recovery of lesions was observed. This improvement lasted until day 6. Lesions were almost completely healed by day 10.

Example 5-Treatment of psoriasis.
An open label study of the True Human™ monoclonal antibody RA-18C3 (specific for IL-1alpha) was conducted in human subjects with moderate to severe chronic plaque psoriasis. Study subjects received 200 mg of RA-18C3 via subcutaneous injection for a total of 3 injections on days 0, 21 and 42. PASI (Psoriasis Area and Severity Index Rating) scores were obtained at various time points for each subject. A reduction in PASI score (ie, improvement in disease) was shown at day 56 for the first 5 evaluable all-subject studies. The average reduction in PASI score at Day 56 for the first 5 evaluable subjects was approximately 50%.

Example 6: Intermediate Phase II Open-Label Study of the Safety, Pharmacokinetics, and Efficacy of the True Human™ Anti-Inflammatory Therapeutic Antibody (RA-18C3) in Subjects With Moderate to Severe Acne Vulgaris result.
RA-18C3 is an injectable stabilized liquid formulation in stabilized isotonic buffer of MABp1. The study population consists of subjects >18 years of age with moderate to severe acne vulgaris. The subjects were candidates for systemic treatment, with an overall investigator evaluation of ≧3, ≧15 for inflammatory lesions on the face. Eleven patients were enrolled. Seven of the 11 subjects enrolled have lesion count data available on day 56 and are included in the analysis. Most patients (86%) were Caucasian, median age was 23 (19-30) years, and 5 (71%) were female. Facial total inflammatory lesion counts were 35±8% on day 42 (median 34%, range 25-48%); and 44±23% on day 56 (median 42%, 19-71%). The average improvement over time).

The Body Image Anxiety Questionnaire (BIDQ) is a self-assessed, clinically validated questionnaire used to assess "negative body image." The internal consistency, reliability and validity of the 7-item body image anxiety questionnaire have been established by several previous studies (as well as its potential usefulness in a clinical setting for qualitative analysis). In recent years, a modified version of BIDQ has been approved for use especially in patients with acne vulgaris. Self-reported measurements of the Modified Body Image Anxiety Questionnaire (collected on Day 0 (D0) and Day 21 (D21)) were analyzed. This seven-item survey tool evaluated various aspects of body image constructs, including appearance concerns, emotional attachment to those concerns, and the resulting social and occupational disabilities. In response to the first question in the BIDQ survey, all 7 subjects reported that acne was the major skin problem and were worried about the appearance of the skin. At D21, 43% showed improvement in mental attachment (Q2), emotional distress (Q3) and social/occupational disability (Q4), whereas 86% showed disability in social life (Q5), school/ It showed stabilization (no further deterioration) in work impairment (Q6), and nullification of aggressiveness due to acne problems (Q7). The average score of the six BIDQ items (Q2 to Q7) showed a significant decrease at D21 from the level of D0. This shows, in general, an improvement in body image anxiety.

It was hypothesized that there was a causal relationship between the underlying inflammatory process present in skin disorders and psychiatric symptoms. To further explore this possibility, the Hospital Anxiety and Depression Scale (HADS) was used to assess the depression and anxiety profiles of the study population. D0 and D21 scores were available for all 7 subjects. The average anxiety scores for D0 and D21 were 6.1±3.1 (median 6.0) and 3.3±3.9 (median 3), respectively (Δ2.9) (FIG. 3). Significant levels of baseline anxiety were predominant in the study population, as observed from the high D0 score (median 6). It is important to note that about a 50% reduction in anxiety (6.1 ± 3.1 to 3.3 ± 3.9) was achieved by D21. Subjects with an improvement in anxiety score of ≧3 points had a substantial (21% to 34%) decrease in D21 “face inflammatory lesion count”. Mean depression scores were 2.6±3.1 (median 1) and 2.1±3.1(1) at D0 and D21, respectively.

Other Embodiments The present invention has been described in conjunction with the detailed description thereof, but the foregoing description is intended to be illustrative and within the scope of the invention, which is defined by the appended claims. It should be understood that it is not intended to be limiting. Other aspects, advantages, and modifications are within the scope of the claims.

Claims (5)

A medicament comprising a pharmaceutically acceptable carrier in the manufacture of a medicament for reducing anxiety in a human subject having acne and an anti-IL-1α antibody in an amount effective to reduce the anxiety in said human subject. Use of the composition. Use according to claim 1, characterized in that the anti -IL-1α antibody is a monoclonal antibody. Use according to claim 2, characterized in that the monoclonal antibody is IgG1. Use according to claim 2, characterized in that the monoclonal antibody comprises the complementarity determining region of MABp1. Use according to claim 2, characterized in that the monoclonal antibody is MABp1.