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Wo 2 11/1 677 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 1 /1 1 September 2011 (01.09.2011) W O 2 1 1/ 1 6 7 7 A l (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07K 1/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US201 1/026521 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 28 February 201 1 (28.02.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/339,073 26 February 2010 (26.02.2010) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, AEROVANCE INC. [US/US]; 2929 7th Street, Suite ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 120, Berkeley, California 94710 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventor; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (75) Inventor/Applicant (for US only): TOMKINSON, Adri¬ SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, an [GB/US]; El Cerrito, California (US). GW, ML, MR, NE, SN, TD, TG). (74) Agents: HALIDAY, Emily, M. et al; WEAVER Published: AUSTIN VILLENEUVE & SAMPSON LLP, P.O. Box 70250, Oakland, California 94612-0250 (US). — with international search report (Art. 21(3)) o o (54) Title: USE OF MODIFIED IL-4 MUTIEN RECEPTOR ANTAGONISTS TO TREAT DERMATITIS (57) Abstract: The present invention provides methods for treating atopic diseases, including atopic dermatitis and other inflam matory or allergic skin disorders by administering mutant human Interleukin-4 (IL-4) compositions that act as antagonists to IL 4 and IL-13. USE OF MODIFIED IL-4 MUTIEN RECEPTOR ANTAGONISTS TO TREAT DERMATITIS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. provisional application no. 61/339,073, filed February 26, 2010, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to methods for treating atopic diseases, including atopic dermatitis and other inflammatory or allergic skin disorders by administering mutant human Interleukin-4 (IL-4) compositions that act as antagonists to IL-4 and IL-13. BACKGROUND OF THE INVENTION [0003] Interleukin-4 (IL-4) is a pleiotropic cytokine with a broad spectrum of biological effects on several target cells, including activation, proliferation and differentiation of T and B cells. IL-4 is increasingly appreciated as a pivotal cytokine initiating the "Th2-type" inflammatory response, whereas IL-13 is now appreciated as the more probable downstream effector cytokine. During proliferation of B- lymphocytes, IL4 acts as a differentiation factor by regulating class switching to the IgGl and IgE isotypes. [0004] Atopic diseases are characterized by formation of IgE antibodies, which results in immediate hypersensitivity reactions upon exposure to specific allergens. The frequent and chronic infections occurring on the skin of atopic disease patients result from the impaired immune response and from the skin barrier breaking down. Known treatments of atopic diseases include, hydrating the skin, dietary restrictions, avoidance of irritants and allergens in the environment, tars, antihistamines, hyposensitization, corticosteroids, antibacterials, antifungals, ultraviolet light, leukotriene blockers, inhibitors of mast cell content release, pentoxifylline, azathioprine, cyclosporin A, cyclophosphamide, tacrolimus, interferon gamma, thymopentin and phosphodiesterase inhibitors. [0005] Generally, anti-histamine and steroidal agents are used as therapeutic treatments for atopic diseases. Anti-histamine agents typically reduce the itchiness of the allergic response and include diphenhydramine hydrochloride, mequitazine, promethazine hydrochloride, and chlorpheniramine maleate. Steroidal agents including prednisolone, hydrocortisone butyrate, dexamethasone valerate, betamethasone dipropionate, clobetasol propionate and the like have also been used to control the itching. While anti-histamine and steroidal agents relieve the itching, they are not desirable therapeutic agents because they cause other adverse side affects including infection, secondary adrenal cortical insufficiency, diabetes, peptic ulcer, hirsutism, alopecia, and pigmentation. SUMMARY OF THE INVENTION [0006] In certain embodiments, the invention provides a method for inhibiting a dermatitis response in a subject. The method entails: administering to a subject in need thereof a therapeutically effective amount of a modified IL-4 mutein receptor antagonist, wherein the modified IL-4 mutein receptor antagonist includes at least the following modifications: (1) substitution of each of the amino acids occurring in the wild-type human IL-4 protein at positions 121 and 124 with different amino acids; (2) substitution of the threonine occurring in the wild-type human IL 4 protein at position 13 with a different amino acid; (3) substitution of the asparagine occurring in the wild-type human IL 4 protein at position 38 with a cysteine; and (4) a non-protein polymer covalently attached to the substituted cysteine at position 38. [0007] In particular embodiments of this method, the modified IL-4 mutein receptor antagonist is co-administered with a therapeutically effective amount of an additional agent that mitigates a symptom of dermatitis. [0008] In other embodiments, the invention provides pharmaceutical composition, which includes: a therapeutically effective amount of a modified IL-4 mutein receptor antagonist, wherein the modified IL-4 mutein receptor antagonist includes at least the following modifications: (1) substitution of each of the amino acids occurring in the wild- type human IL-4 protein at positions 121 and 124 with different amino acids; (2) substitution of the threonine occurring in the wild-type human IL 4 protein at position 13 with a different amino acid; (3) substitution of the asparagine occurring in the wild-type human IL 4 protein at position 38 with a cysteine; and (4) a non-protein polymer covalently attached to the substituted cysteine at position 38; and a therapeutically effective amount of an additional agent that is useful for mitigating a symptom of dermatitis. The therapeutically effective amount of the modified IL-4 mutein receptor antagonist is sufficient to mitigate a symptom of dermatitis, and the therapeutically effective amount of the additional agent is sufficient to mitigate a symptom of dermatitis. [0009] In yet other embodiments, the invention provides a kit that includes: at least one unit dosage form comprising a therapeutically effective amount of a modified IL-4 mutein receptor antagonist, wherein the modified IL-4 mutein receptor antagonist comprises at least the following modifications: (1) substitution of each of the amino acids occurring in the wild- type human IL-4 protein at positions 121 and 124 with different amino acids; (2) substitution of the threonine occurring in the wild-type human IL 4 protein at position 13 with a different amino acid; (3) substitution of the asparagine occurring in the wild-type human IL 4 protein at position 38 with a cysteine; and (4) a non-protein polymer covalently attached to the substituted cysteine at position 38; and at least one unit dosage form comprising a therapeutically effective amount of an additional agent that is useful for mitigating a symptom of dermatitis. The therapeutically effective amount of the modified IL-4 mutein receptor antagonist is sufficient to mitigate a symptom of dermatitis, and the therapeutically effective amount of the additional agent is sufficient to mitigate a symptom of dermatitis. BRIEF DESCRIPTION OF THE DRAWINGS [0010] Figure 1 shows a schematic representation of the chemistry of a PEGylation reaction. [0011] Figure 2 is a graphical diagram showing data from BIAcore binding to IL-4Ra comparing the IL-4 double mutein (IL-4DM) to the same molecule with a 30kD linear or a 40kD branched PEG at position 38C. [0012] Figure 3 is a graphical diagram showing data from inhibition of TF-1 growth with IL-4 stimulation revealing that PEGylated IL-4TM (T13D/R121D/Y124D) is more potent than PEGylated IL-4DM and is equally potent to IL-4DM (R121D/Y124D). [0013] Figure 4A-4B: AER 003 Model. Model of AER 003 derived from the structure of human IL-4 is shown. (A) Residues implicated in the antagonist activity are highlighted in yellow (AER 001). The mutation T13D (red) results in increased binding to IL-4R a, while N38C (green) serves as an attachment point for PEG. (B) Pegylated AER 003. [0014] Figure 5 : Study design. AER 003 biological activity was evaluated in a primate model of AHR and inflammation using a double-blind, 2-period cross-over design (A). All animals were rested at least 8 weeks between studies to allow airway responsiveness and inflammation to return to baseline (pre-allergen) levels. Studies were performed using the 7 day primate asthma model (B). Airway responsiveness to inhaled MCh and airway cellular composition by BAL were determined 2 days before (Day 0) and 2 days after (Day 7) three consecutive-day (Days 3, 4, 5) inhalations of Ascaris suum extract. AER 003 (2 mg/kg) or vehicle was administered subcutaneously 48 h prior to the first antigen challenge (Day 1).
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