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WO 2007/149032 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 27 December 2007 (27.12.2007) PCT WO 2007/149032 Al (51) International Patent Classification: [GB/GB]; Cambridge Antibody Technology Ltd., Milstein C07K 16/24 (2006.01) A61K 39/395 (2006.01) Building, Granta Park, Cambridge CB21 6GH (GB). (21) International Application Number: (74) Agent: ASTRAZENECA AB; Global Intellectual Prop PCT/SE2007/000600 erty, S-151 85 Sodertalje (SE). (22) International Filing Date: 20 June 2007 (20.06.2007) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (25) Filing Language: English CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, (26) Publication Language: English IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, MG, MK, MN, MW, MX, (30) Priority Data: MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, 60/815,828 23 June 2006 (23.06.2006) US RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, 60/913,566 24 April 2007 (24.04.2007) US TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (71) Applicants (for all designated States except US): AS- (84) Designated States (unless otherwise indicated, for every TRAZENECA AB [SE/SE]; S-151 85 Sodertalje (SE). kind of regional protection available): ARIPO (BW, GH, CAMBRIDGE ANTIBODY TECHNOLOGY LTD. GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, [GB/GB]; Milstein Building, Granta Park, Cambridge ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), CB21 6GH (GB). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (72) Inventors; and PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, (75) Inventors/Applicants (for US only): COCHRANE, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Duncan [GB/GB]; Cambridge Antibody Technology Ltd., Milstein Building, Granta Park, Cambridge CB21 6GH Published: (GB). DUFNER, Patrick [CWCH]; Scheffelstrasse 11, — with international search report CH-8037 Zurich (CH). LANGHAM, Caroline [GB/GB]; — before the expiration of the time limit for amending the AstraZeneca R & D Alderley, Alderley Park, Maccles- claims and to be republished in the event of receipt of field, Cheshire SKlO 4TG (GB). NEEDHAM, Maurice amendments [GB/GB]; AstraZeneca R & D Alderley, Alderley Park, — with sequence listing part of description published sep a Macclesfield, Cheshire SKlO 4TG (GB). RUSSELL, rately in electronic form and available upon request from Caroline [GB/GB]; Cambridge Antibody Technology the International Bureau Ltd., Milstein Building, Granta Park, Cambridge CB21 6GH (GB). SLEEMAN, Matthew [GB/GB]; Cambridge For two-letter codes and other abbreviations, refer to the "G uid Antibody Technology Ltd., Milstein Building, Granta ance Notes on Codes and Abbreviations" appearing at the beg in Park, Cambridge CB21 6GH (GB). WELSH, Fraser ning of each regular issue of the PCT Gazette. (54) Title: ANTIBODY MOLECULES FOR HUMAN IL-17 (57) Abstract: Binding members, especially antibody molecules, for interleukin 17 (IL-17). The binding members are useful for the treatment of disorders associated with interleukin 17 such as rheumatoid arthritis. Antibody molecules for human IL- 17 This invention relates to binding members for interleukin 17 (IL-17, also referred to as IL-17A) , especially antibody molecules, and their therapeutic use e.g. in treating disorders associated with IL-17 such as rheumatoid arthritis . IL-17A is a T-cell derived cytokine, which has pleiotropic pro¬ inflammatory activities. In vitro, IL-17A regulates production of inflammatory mediators from fibroblasts and synoviocytes, can synergise with other pro-inflammatory cytokines, and can promote cartilage degradation and osteoclastic bone resorption. IL-17A is a homodimer consisting of two 155 amino acid chains. Each polypeptide chain includes a 23 amino acid N-terminal peptide which is cleaved to produce a mature polypeptide of 132 residues. IL-17A binds to and exerts its effects via activation of the IL-17 receptors A and C (Toy et al 2006J . Five homologues of IL-17A exist, designated IL-17B to IL-17F, all with divergent and distinct biological roles. Swissprot accession numbers for the IL-17 homologues are: IL-17B Q9UHF5; IL-17C Q96P0M4; IL-17D Q8TAD2; IL-17E Q9H293; IL-17F Q96PD4. IL-17B and IL-17C have a wide tissue expression with the cellular origin of the proteins unknown, although IL-17B transcripts can be found at high levels in the nervous system (Moore e t al 2002) . IL-17B and IL-17C can induce TNFα from the monocytic cell line THP-I (Li et al 2000), and induce neutrophilia when injected into mouse models (Shi et al 2000) . IL-17D is detected in multiple tissues and is expressed in resting CD4+ T cells and CD19+ B cells (Starnes et al 2002) . IL-17E (IL-25) elicits Th2 type responses such as airway hyper responsiveness and eosinophilia and has properties distinct to the other family members (Fort et al 2001) . IL-17F exists as two isoforms and exhibits greatest homology with IL-17A (55 and 40% homology) and shares many similar functional properties such as induction of neutrophilia in the lung and induction of pro inflammatory cytokines including IL-8 (Hymowitz et al 2001; Hurst e t al 2002, Oda et al. 2005) . IL-17 family members may have a role in innate and adaptive immunity hence an antibody targeting only IL-17A will ensure the specific effects of IL-17A signalling are suppressed in areas where IL-17A is expressed. Binding between family members and the IL-17 receptor family is not fully understood. IL-17E is known to signal via IL-17RB although IL- 17B has also been reported to bind with lower affinity (Lee et al. 2001) . IL-17A has been reported to bind IL-17RC (IL-17RL) in addition to IL-17RA and similarly IL-17F shares binding to these receptors (Toy et al. 2006, Kuestner e t al. 2005) . Further receptors, IL-17RD and IL-17RE exist although their endogenous ligands are yet to be identified. Multiple splice variants exist for IL-17RC and IL-17RD (Haudenschild et al. 2002; Haudenschild et al. 2006; Moseley et al. 2003) . Binding of IL-17A to its receptor is likely to induce oligomerisation of the receptor resulting in its activation. Activation of IL-17RA by IL-17A activates a number of pro-inflammatory signal pathways such as the extracellular signal-regulated protein kinase (ERKl/2) , c-jun N-terminal kinase (JNK) and p38 MAP kinase pathways. Activation of these pathways triggers changes in the expression levels of a range of pro-inflammatory genes and proteins, via mechanisms which are not completely defined. IL-17A is secreted primarily by CD4+ and CD8+ T cells (Lubberts et al. 2001). IL-17A, either as its RNA or intracellular protein, has also been detected in neutrophils, eosinophils and human blood monocytes (Molet et al. 2001; Ferretti et al. 2003). IL-6 and TGF β have recently been implicated in differentiation of naϊ ve T cells into IL-17 producing T cells (Betteli et al. 2006), while two further cytokines implicated in rheumatoid arthritis, IL-15 and IL-23, regulate the release of IL-17A from T lymphocytes. IL-17A upregulates inflammatory cytokine production and prostaglandin production from synovial fibroblasts, enhances MMP production from synovial fibroblasts and articular chondrocytes and may play a role in osteoclastic bone resorption. In the context of the inflammatory milieu in rheumatoid arthritis (RA) tissue, IL-17A may have a particular role in synergising with other pro-inflammatory cytokines notably TNF-α and IL-l β . Several lines of evidence suggest an important role for IL-17 in the pathogenesis of rheumatoid arthritis (RA) . Functional IL-17A was spontaneously secreted by 16/18 RA synovial explants compared to 2/12 OA explants and 0/3 normal synovial explants. Immunostaining of RA synovium revealed IL-17A producing cells in the T cell rich area (Chabaud et al. 1999) . The level of IL-17A in serum of RA patients is elevated compared with normal control serum (Cho et al. 2004) . IL-17A has been shown to stimulate the release of a range of pro inflammatory cytokines. 1L-17A, sometimes acting in synergy with other cytokines, enhances IL-I, IL-6, and LIF production from synovial fibroblasts (Katz et al. 2001; Chabaud et al. 1998). Additionally, IL-17A has been shown to upregulate COX-2 expression in inflammatory cells. IL-17A induces COX-2 gene expression in human chondrocytes, synovial fibroblasts and macrophages and human synovial explants (e.g. Faour et al. 2003; Le Grand et al. 2001). Recombinant IL-17A upregulates synoviocyte COX-2 expression and enhances TNFα-stimulated synoviocyte COX-2 expression (Stamp et al. 2004) . In addition to these "classical" pro-inflammatory activities, IL-17A also elicits other effects in the RA joint such as promoting degradation of cartilage. IL-17 has also been shown to be involved in the upregulation of MMPs and impact on cartilage degradation. IL-17A increases spontaneous production of MMPl by human RA synoviocytes. IL-17A co-ordinately upregulates MMP3, MMP13 and ADAMTS4 genes in bovine articular chondrocytes (Sylvester et al. 2004) . IL-17A is a potent inducer of matrix breakdown and an inhibitor of matrix synthesis in articular cartilage explants (Cai et al.
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