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Wsx-1/Il-27 As a Target for Anti-Inflammatory Responses

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Wsx-1/Il-27 As a Target for Anti-Inflammatory Responses (19) TZZ ZZ_T (11) EP 2 046 809 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 1/00 (2006.01) C07K 14/54 (2006.01) 07.12.2016 Bulletin 2016/49 C07K 14/715 (2006.01) C07K 16/24 (2006.01) (21) Application number: 07836143.3 (86) International application number: PCT/US2007/016329 (22) Date of filing: 18.07.2007 (87) International publication number: WO 2008/011081 (24.01.2008 Gazette 2008/04) (54) WSX-1/IL-27 AS A TARGET FOR ANTI-INFLAMMATORY RESPONSES WSX-1/IL-27 ALS TARGET FÜR ENTZÜNDUNGSHEMMENDE REAKTIONEN WSX-1/IL-27 UTILISÉ COMME CIBLE POUR SUSCITER DES RÉACTIONS ANTI-INFLAMMATOIRES (84) Designated Contracting States: • VILLARINO ALEJANDRO V ET AL: "IL-27 limits AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IL-2 production during Th1 differentiation." HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE JOURNALOF IMMUNOLOGY (BALTIMORE, MD. : SI SK TR 1950) 1 JAN 2006, vol. 176, no. 1, 1 January 2006 Designated Extension States: (2006-01-01), pages 237-247, XP002570061 ISSN: AL BA RS 0022-1767 • KASTELEIN ROBERT A ET AL: "Discovery and (30) Priority: 19.07.2006 US 832213 P biologyof IL-23 andIL-27: relatedbut functionally 11.08.2006 US 837450 P distinct regulators of inflammation." ANNUAL REVIEW OF IMMUNOLOGY 2007, vol. 25, 2007, (43) Date of publication of application: pages 221-242, XP002570062 ISSN: 0732-0582 15.04.2009 Bulletin 2009/16 • SCHELLER J ET AL: "No inhibition of IL-27 signaling by soluble gp130" BIOCHEMICAL AND (73) Proprietor: The Trustees of The University of BIOPHYSICAL RESEARCH COMMUNICATIONS, Pennsylvania ACADEMIC PRESS INC. ORLANDO, FL, US, vol. Philadelphia PA 19104-6283 (US) 326, no. 4, 28 January 2005 (2005-01-28), pages 724-728, XP004682873 ISSN: 0006-291X (72) Inventors: • "Abstracts of the AGA Institute" • HUNTER, Christopher, A. GASTROENTEROLOGY, ELSEVIER, Swarthmore, PA 19081 (US) PHILADELPHIA, PA, vol. 130, no. 4, 1 April 2006 • STUMHOFER, Jason, Scott (2006-04-01) , pages A-1, XP005643844 ISSN: Plymouth Meeting, PA 19462 (US) 0016-5085 • DELACRUZ J S ET AL: "Antibody-cytokine fusion (74) Representative: Westphal, Mussgnug & Partner proteins: innovative weapons in the war against Patentanwälte mbB cancer" CLINICAL AND EXPERIMENTAL Herzog-Wilhelm-Strasse 26 MEDICINE, SPRINGER VERLAG, MILAN, IT, vol. 80331 München (DE) 4, no. 2, 1 October 2004 (2004-10-01) , pages 57-64, XP002470981 ISSN: 1591-8890 (56) References cited: • HUNTER CHRISTOPHER A: "New IL-12-family WO-A2-99/02552 WO-A2-2004/069173 members: IL-23 and IL-27, cytokines with WO-A2-2005/079848 US-A- 5 686 575 divergent functions" NATURE REVIEWS. US-A1- 2002 164 609 US-A1- 2004 234 522 IMMUNOLOGY, NATURE PUBLISHING GROUP, GB, vol. 5, no. 7, 1 July 2005 (2005-07-01), pages 521-531, XP002455691 ISSN: 1474-1733 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 046 809 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 046 809 B1 • PFLANZ S.: ’IL-27, a heterodimerc cytokine Remarks: composed of EB13 and p28 protein, induces Thefile contains technical information submitted after proliferationof Naive CD4+ T cells’ IMMUNITY vol. the application was filed and not included in this 16, June 2002, pages 779 - 790, XP002982845 specification 2 EP 2 046 809 B1 Description FIELD OF THE INVENTION 5 [0001] The invention relates to isolated or recombinant complexes including soluble WSX-1 or isolated or recombinant WSX-1 fusion proteins for use in treating inflammatory conditions. BACKGROUND OF THE INVENTION 10 [0002] A number of recombinant cytokines are used in a variety of clinical settings. These include interleukin-2 (IL-2), GM-CSF, IL-11, IL-12 and type I interferons (IFNs). These proteins are primarily being used as stimulators of immune cells and to act as growth factors or to enhance anti-cancer or viral responses. Few cytokines have been used to inhibit the immune system; for example, inhibition has been attempted with IL-10, which works indirectly on accessory cell functions necessary for T cell functions and which was being developed specifically with Crohn’s disease and Inflam- 15 matory Bowel Disease as targets, and TGF. Success with these has been limited. [0003] Antagonists of IL-12 p40 have been tested in clinical trials for patients with Crohn’s disease with some success. [0004] Antagonists of IL-15 are in clinical trials for arthritis based on the observation that this cytokine was involved in the development of this disease. [0005] The IL-1 receptor antagonist is a commercially available product that is used to treat patients with rheumatoid 20 arthritis. This is a product that blocks the interaction of the pro-inflammatory cytokine IL-1 with its receptor. [0006] Several companies have developed antibodies/antagonists specific for the cytokine TNF- α which are currently used in the treatment of patients with rheumatoid arthritis. This approach relies on the neutralization of endogenous cytokine to prevent inflammation. A similar approach has been pursued with antibodies specific for IL-1 and IL-6. One safety issue is that these treatments are associated with the development of opportunistic infections including TB and 25 toxoplasmosis. Further, Villarino AV et al. (J Immunol 2006; 176:237-247) relates to the problem of treating an inflam- matory disease by inhibition of immunopathologic mechanisms through IL-27 signaling and describe cellular mechanisms for the anti-inflammatory effects of IL-27. SUMMARY OF THE INVENTION 30 [0007] WSX-1 is a recently described cytokine receptor which binds to the heterodimeric cytokine IL-27. Our studies have suggested that this cytokine/receptor pair is involved in the negative regulation of T cell mediated inflammatory responses. The identification of a role for WSX-1 in the suppression of T cell hyperactivity has clinical implications for T cell-mediated inflammatory disorders and represents a novel target for immune based therapies. Work from this 35 laboratory has continued to focus on the inhibitory effects of IL-27 in different T cell responses, and we have made several observations that have provided new insights into the biology of this cytokine receptor system and suggested new ways to use this information to develop anti-inflammatory therapies. [0008] It is clear from our studies that WSX-1 has a negative effect on T cell responses. IL-27 can inhibit Th1 and Th2 responses and the ability of these cells to make the T cell growth factor IL-2. In addition, IL-27 inhibits a new T cell subset 40 - T17 (T cells that produce IL-17) - that is thought to be a major pathological T cell subset. A fusion protein, WSX-1Fc, is able to enhance the ability of IL-27 to inhibit T cell production of IL-2 and IFN γ. This implies that a shed version of this receptor may facilitate IL-27 or its individual components to signal T cells. This is in part based on the biology of the closely related cytokine/receptor component for IL-6 activity. This idea is supported by the observation that recombinant p28 (supplied by eBioscience, and also known as IL-30), while not as efficient as IL-27, is able to antagonize the 45 production of IL-2 and IL-17. These data imply to us that p28 alone, modified, or as part of another molecule or complex that includes WSX-1, represents a useful therapeutic approach to modulate cells of the immune system. Similarly, soluble WSX-1 polypeptides and complexes also represent a useful therapeutic approach. Since IL-27 can signal through a receptor complex including both WSX-1 and gp130, soluble gp130 polypeptides and complexes represent yet another useful therapeutic approach. 50 [0009] Accordingly, the present invention provides a composition for use in the treatment of an inflammatory condition comprising an isolated or recombinant soluble WSX-1/IL-27 complex, wherein the inflammatory condition is selected from: an immunedisorder; an infection; cancer; an allergy; arthritis; asthma; inflammatorybowel disease, Crohn’s disease; uveitis; psoriasis; lupus; multiple sclerosis; a chronic infectious disease; tuberculosis; ankalyzing spondalitis; transplant rejection; sarcoidosis; hepatitis. 55 [0010] In one aspect, the composition is anti-inflammatory. The composition optionally includes a pharmaceutically acceptable excipient, for example, in embodiments in which the composition is to be administered to a subject. In one embodiment, the composition suppresses development of IL-17 cells from naive T cells induced by IL-6 and transforming growth factor beta. 3 EP 2 046 809 B1 [0011] The composition can include one or more cell, for example, one or more T cell, B cell, mast cell, neutrophil, macrophage, dendritic cell, or other cell expressing gp130 or WSX-1. The complex can affect a function or activity of the cell. In one embodiment, the composition includes a T-cell, and the composition alters a function or activity of the T-cell. For example, the T-cell can display altered expression of IL-2, IFN-gamma, TNF-alpha, IL-6, IL-4, IL-13, IL-17, 5 IL-25, IL-10, IL-5, or CD25, altered proliferation, or altered survival. The composition optionally includes transforming growth factor beta. [0012] One class of embodiments provides a recombinant or isolated WSX-1 fusion protein for use in the treatment of an inflammatory condition, , wherein the inflammatory condition is selected from: an immune disorder; an infection; cancer; an allergy; arthritis; asthma; inflammatory bowel disease, Crohn’s disease; uveitis; psoriasis; lupus; multiple 10 sclerosis; a chronic infectious disease; tuberculosis; ankalyzing spondalitis; transplant rejection; sarcoidosis; hepatitis.
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