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WO 2018/083248 Al 11 May 2018 (11.05.2018) W !P O IPCT

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WO 2018/083248 Al 11 May 2018 (11.05.2018) W !P O IPCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2018/083248 Al 11 May 2018 (11.05.2018) W !P O IPCT (51) International Patent Classification: for Childhood Cancer Research, Seattle Children's Hospital, A61K 39/395 (2006.01) C07K 16/28 (2006.01) 2001 Eighth Avenue, Suite 400, Seattle, Washington 98121 A61K 31/436 (2006.01) A61P 37/06 (2006.01) (US). TKACHEV, Victor; Ben Towne Center for Child hood Cancer Research, Seattle Children's Hospital, 2001 (21) International Application Number: Eighth Avenue, Suite 400, Seattle, Washington 98121 (US). PCT/EP20 17/078202 (74) Agent: THOMAS, Philip, John, Duval; Potter Clarkson (22) International Filing Date: LLP, The Belgrave Centre, Talbot Street, Nottingham NG1 03 November 2017 (03.1 1.2017) 5GG (GB). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (30) Priority Data: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, 1618529.0 03 November 2016 (03 .11.20 16) GB DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 1702965.3 23 February 2017 (23.02.2017) GB HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 1706639.0 26 April 2017 (26.04.2017) GB KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 1710953.9 07 July 2017 (07.07.2017) GB MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 1713 147.5 16 August 2017 (16.08.2017) GB OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (71) Applicant: KYMAB LIMITED [GB/GB]; The Bennet SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, Building (B930), Babraham Research Campus, Cambridge TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. CB22 3AT (GB). (84) Designated States (unless otherwise indicated, for every (72) Inventors: BLAND-WARD, Philip; The Bennet Build kind of regional protection available): ARIPO (BW, GH, ing (B930), Babraham Research Campus, Babraham, Cam GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, bridge CB22 3AT (GB). KEAN, Leslie; Ben Towne Center UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (54) Title: ANTIBODIES, COMBINATIONS COMPRISING ANTIBODIES, BIOMARKERS, USES & METHODS Figure 1 E ffe c t o f a n t i-O X 4 0 L a n t ib o d ie s o n th e O X 4 0 L /O X 4 0 R b in d in g Is o ty p e lg G 4 P E c o ntro l a n tib o d y 1 Ig G 1 10 A 0 7 lg G 4 P E 2 D 1 0 lg G 4 P E 00 mr ¾ oo © Log (c o nce ntra tio n M) 00 o (57) Abstract: The present invention relates to combinations comprising anti-human OX40L antibodies, new biomarkers of autoim o mune or alloimmune diseases, and their use in various therapeutic methods. [Continued on nextpage] WO 2018/083248 Al llll II II 11III II I III III 11III I III II I II TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) ANTIBODIES, COMBINATIONS COMPRISING ANTIBODIES, BIOMARKERS. USES & METHODS The present invention relates to combinations comprising anti-human OX40 or anti-human OX40L antibodies, new medical uses and methods. BACKGROUND OX40 ligand (OX40L) is a TNF family member; a 34 kDa type II transmembrane protein. The crystallized complex of human OX40 and OX40L is a trimeric configuration of one OX40L (trimer) and three OX40 monomers. The human extracellular domain is 42% homologous to mouse OX40L. OX40L is not constitutively expressed but can be induced on professional APCs such as B- cells, dendritic cells (DCs) and macrophages. Other cell types such as Langerhans cells, endothelial cells, smooth muscle cells, mast cells and natural killer (NK) cells can be induced to express OX40L. T-cells can also express OX40L. The OX40L receptor, OX40, is expressed on activated T-cells (CD4+ and CD8+ T-cells, Th2, Thl and Thl7 cells) and CD4+ Foxp3+ cells, even in the absence of activation. The interaction between OX40 and OX40L occurs during the T-cell-DC interaction 2 or 3 days after antigen recognition. After leaving DCs, the OX40-expressing T-cell may interact with an OX40L- expressing cell other than a DC and receive an OX40 signal from this cell, which may provide essential signals for the generation of memory T-cells, the enhancement of Th2 response and the prolongation of the inflammatory responses. OX40 signals into responder T-cells render them resistant to Treg mediated suppression. Graft versus host disease is a major cause of mortality following allogeneic bone marrow treatment. I n the acute version of the disease, mature T-cells present in the bone marrow graft recognise the donor tissue as foreign in an environment of damaged tissue, which, via host APCs cause the activation and proliferation of the donor T-cells, with subsequent T-cell migration into the liver, spleen, gut, skin and lungs, causing tissue damage by the CTL effector response and inflammatory cytokine/chemokine release. Onset for acute disease is usually within the first 100 days post transplantation (Hill-Ferrara, Blood May 1, 2000 vol. 95 no. 9 2754-275, Reddy-Ferrara Blood, Volume 17, Issue 4, December 2003). Chronic GvHD usually appears 100 days post transplantation and several factors are thought to be involved, including thymic damage caused by prior acute GvHD which results in a reduced clearance of pathogenic T-cells (Zhang et al, September 1, 2007 vol. 179 no. 5 3305-3314), up- regulation of TGF-β, which causes fibrosis (McCormick etal J Immuno, November 15, 1999 vol. 163 no. 10 5693-5699), and a B-cell component driven by elevated B-Cell activating factor (BAFF) (Sarantopoulos etal, Clin Cancer Res October 15, 2007 13; 6107) as well as auto-antibodies against platelet derived growth factor receptor (Svegliati etal, Blood July 1, 2007 vol. 110 no. 1 237-241). Clinical studies have shown that OX40 is up-regulated in both acute (Morante etal, Clinical and Experimental Immunology,145:36-43) and chronic (Kotani etal, Blood November 15, 2001 vol. 98 no. 10 3162-3164) GvHD. Administration of an antagonistic anti-OX40L enhanced survival in a lethal acute mouse model of GvHD, with a 70% survival in the treated group compared t o the untreated who all died by day 43 (Tsukada etal, Blood, 1 April 2000, Volume 95, Number 7) whereas treatment with an agonistic anti-OX40 Ab accelerated the disease and mortality (Blazar et al Blood May 1, 2003 vol. 101 no. 9 3741-3748). Blockade of the OX40-OX40L interaction has been shown to be efficacious in several other inflammatory diseases, with anti-OX40L Ab being used to treat a mouse model of colitis (Totsuka etal., AJP - GI April 1, 2003 vol. 284 no. 4 G595-G603), and that an anti- OX40L Ab could block the development of diabetes in NOD mice (Pakala et al European Journal of Immunology Volume 34, Issue 11, pages 3039-3046, November 2004). References Lamb, L.S., Abhyankar, S.A., Hazlett, L , O'Neal, W., Folk, R.S., Vogt, S., Parrish, R.S., Bridges, K., Henslee-Downey, P.J. and Gee, A. P. (1999), Expression of CD134 (0X-40) on T-cells during the first 100 days following allogeneic bone marrow transplantation as a marker for lymphocyte activation and therapy-resistant graft-versus-host disease. Cytometry, 38: 238-243. Xupeng Ge, Julia Brown, Megan Sykes, Vassiliki A . Boussiotis, CD134-Allodepletion Allows Selective Elimination of Alloreactive Human T-cells without Loss of Virus-Specific and Leukemia- Specific Effectors, Biology of Blood and Marrow Transplantation, Volume 14, Issue 5, May 2008, Pages 518-530. Naoto Ishii, Takeshi Takahashi, Pejman Soroosh, Kazuo Sugamura, Chapter 3 - OX40-OX40 Ligand Interaction in T-Cell-Mediated Immunity and Immunopathology, In: Frederick W. Alt, Editor(s), Advances in Immunology, Academic Press, 2010, Volume 105, Pages 63-98. Croft, M., So, T., Duan, W. and Soroosh, P. (2009), The significance of OX40 and OX40L to T-cell biology and immune disease. Immunological Reviews, 229: 173-191. SUMMARY OF THE INVENTION The invention provides anti-human OX40L (hOX40L) antibodies and fragments and novel medical applications for treating or preventing hOX40L-mediated diseases or conditions in humans. To this end, the invention provides: - I n a first configuration An antibody or a fragment thereof that specifically binds t o hOX40L for treating or preventing a hOX40L-mediated disease or condition in a human in a method wherein the antibody or fragment is administered to said human, wherein the antibody or fragment is for treating or preventing said hOX40L-mediated disease or condition by decreasing one, more or all of a. secretion of a cytokine selected from TNF alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-13, IL-17, RANTES and interferon gamma in the human; b.
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