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WO 2009/026303 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 26 February 2009 (26.02.2009) PCT WO 2009/026303 Al (51) International Patent Classification: Oaks, CA 91362 (US). SMOTHERS, James, F. [US/US]; C07K 16/28 (2006.01) A61P 35/00 (2006.01) 50 Hilltop Street, Quincy, MA 02169 (US). MEHLIN, A61K 39/395 (2006.01) C07K 14/715 (2006.01) Christopher [US/US]; 2806 NW 61st Street, Seattle, WA 98107 (US). (21) International Application Number: PCT/US2008/07361 1 (74) Agent: AUSENHUS, Scott, L.; AMGEN INC., 1201 Am gen Court W , Seattle, WA 98119 (US). (22) International Filing Date: 19 August 2008 (19.08.2008) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (30) Priority Data: EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, 60/957,148 2 1 August 2007 (21.08.2007) US IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, 61/084,588 29 July 2008 (29.07.2008) US LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, (71) Applicant (for all designated States except US): AMGEN MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, INC. [US/US]; One Amgen Center Drive, Msc 27-4-a, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, Thousand Oaks, CA 91320-1799 (US). TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (72) Inventors; and ZW (75) Inventors/Applicants (for US only): BRASEL, Kenneth, (84) Designated States (unless otherwise indicated, for every Allan [US/US]; 3035 NW 57th Street, Seattle, WA 98107 kind of regional protection available): ARIPO (BW, GH, (US). FOSTER, Stephen [US/US]; 4138 Cedargate Drive, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, Fort Collins, CO 80526 (US). CERRETTI, Douglas, Pat ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), [US/US] ; 1607 North 197th Place, Seattle, WA 98133 (US). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, SUN, Jilin [US/US]; 3250 Woodbluff Court, Thousand FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, [Continued on next page] (54) Title: HUMAN C-FMS ANTIGEN BINDING PROTEINS CynoBM Assay: Titration of c-fms Antibodies In Concentration (ng/ml) FIGURE 4 (57) Abstract: Antigen binding proteins that bind to human c-fms protein are provided. Nucleic acids encoding the antigen binding protein, vectors, and cells encoding the same are also provided. The antigen binding proteins can inhibit binding of c-fms to CSF-I, reduce monocyte migration into tumors, and reduce the accumulation of tumor-associated macrophages. NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, — with sequence listing part of description published sepa- CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). rately in electronicform and available upon requestfrom Published n e International Bureau HUMAN C-FMS ANTIGEN BINDING PROTEINS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 60/957,148 filed on August 21, 2007, and U.S. Provisional Application No. 61/084,588 filed on July 29, 2008 which are incorporated herein by reference in their entireties for all purposes. BACKGROUND [0002] Many human and mouse tumor cell lines secrete the cytokine CSF-I (Colony Stimulating Factor-1, also known as Macrophage-Colony Stimulating Factor, M-CSF) that in turn attracts, promotes the survival, and activates monocyte/macrophage cells through the receptor c-fms (Feline McDonough Strain). Tumor associated macrophages (TAMs) (also known as tumor infiltrating macrophages (TIMs)) can be the major component of the tumor stroma comprising as much as 50% of the cell tumor mass. Kelly et al, 1988, Br. J. Cancer 57:174-177; Leek et al, 1994, J. Leukoc. Biol. 56:423- 435. In surveys of primary human tumors, there is widespread evidence for CSF-I mRNA expression. In addition, many studies have demonstrated that elevated serum CSF-I, the number of TAMs, or the presence of tissue CSF-I and/or c-fms are associated with a poor prognosis for cancer patients. [0003] TAMs support tumor growth, metastasis and survival by a variety of means, including direct mitogenic activity on tumor cells through secretion of PDGF, TGF- β and EGF and metastasis through production of ECM-degrading enzymes (reviewed in Leek and Harris, 2002, J. Mammary Gland Biol and Neoplasia 7:177-189 and Lewis and Pollard, 2006, Cancer Res 66:605-612). Another important means of tumor support by TAMs is the contribution to neo-vascularization of tumors via production of various proangiogenic factors such as COX-2, VEGFs, FGFs, EGF, nitric oxide, angiopoietins, and MMPs. Dranoff et al., 2004, Nat. Rev. Cancer 4:11-22; MacMicking et al., 1997, Annu. Rev. Immunol. 15:323-350; Mantovani et al., 1992, Immunol. Today 13:265-270. In addition, CSF- 1-derived macrophages can be immunosuppressive via production of various factors such as prostaglandins, indolamine 2,3 dioxigenase, nitric oxide, IL-10, and TGF β. MacMicking et al., 1997, Annu. Rev. Immunol. 15:323-350; Bronte et al, 2001, J. Immunother. 24:431-446. [0004] CSF-I is expressed both as a membrane-bound and as a soluble cytokine (Cerretti et al, 1988, MoI. Immunol. 25:761-770; Dobbin et al, 2005, Bioinformatics 21:2430-2437; Wong et al, 1987, Biochem. Pharmacol. 36:4325-4329) and regulates the survival, proliferation, chemotaxis and activation of macrophages and their precursors (Bourette et al, 2000, Growth Factors 17:155-166; Cecchini et /.,1994, Development 120:1357-1372; Hamilton, 1997, J. Leukoc. Biol. 62:145-155; Hume, 1985, Sc/. Prog. 69:485-494; Sasmono and Hume, in: The innate immune response to infection (eds. Kaufmann, S., Gordon, S. & Medzhitov, R.) 71-94 (ASM Press, New York, 2004); Ross and Auger, in: The macrophage (eds. Burke, B. & Lewis, C.) (Oxford University Press, Oxford, 2002)). [0005] The cognate receptor, which is the c-fms proto-oncogene (also known as M-CSFR, CSF-IR or CDl 15), is a 165-kD glycoprotein with an associated tyrosine kinase activity and belongs to the class III receptor tyrosine kinase family that includes PDGFR-α, PDGFR- β, VEGFRl, VEGFR2, VEGFR3, Flt3 and c-kit. Blume-Jensen and Hunter, 2001, Nature 411:355-365; Schlessinger and Ullrich, 1992, Neuron 9:383-391; Sherr et al, 1985 Cell 41:665-676; van der Geer et al, 1994, Annu. Rev. Cell. Biol. 10:251-337. The oncogenic form of c-fms, v-fms, which is carried by the McDonough strain of feline sarcoma virus is mutated to confer constitutively activated protein kinase activity (Sherr et al., 1985, Cell 4J_:665-676; Roussel and Sherr, 2003, Cell Cycle 2: 5-6). Expression of c-fms in normal cells is restricted to myelomonocytic cells (including monocytes, tissue macrophages, Kupffer cells, Langerhans cells, microglial cells and osteoclasts), hematopoietic precursors and trophoblasts. Arai et al., 1999, J. Exp. Med. 190:1741-1754; Dai et al., 2002, Blood 99:1 1 1-120; Pixley and Stanley, 2004, Trends Cell Biol. 14:628-638. Expression of c-fms has also been demonstrated in some tumor cells (Kirma et al., 2007, Cancer Res 67:1918-1926). A variety of in vitro studies and analyses of mutant mice demonstrate that CSF-I is a ligand for c-fms( see, e.g., Bourette and Rohrschneider, 2000, Growth Factors 17:155- 166; Wiktor-Jedrzejczak et al., 1990, Proc. Natl. Acad. ScL U.S.A. 87:4828-4832; Yoshida et al., 1990, Nature 345:442-444; van Wesenbeeck and van HuI, 2005, Crit. Rev. Eukaryot. Gene Expr. 15:133-162). Binding of CSF-I to c-fms induces autophosphorylation of the receptor at particular sites that result in downstream activation of signaling pathways including PI3-K/AKT and Ras/Raf/MEK/MAPK and macrophage differentiation is mediated primarily through persistent MEK activity (Gosse et al., 2005, Cellular Signaling 17:1352-1362). Very recent evidence indicates that interleukin-34 (IL-34) is also a ligand for c-fms (Lin, et al. 2008, Science 320:807-81 1). SUMMARY [0006] Antigen-binding proteins that bind c-fms, including human c-fms, are described herein. The human c-fms antigen-binding proteins were found to inhibit, interfere with, or modulate at least one of the biological responses related to c-fms, and, as such, are useful for ameliorating the effects of c-fms-related diseases or disorders. Binding of certain antigen-binding proteins to c-fms can, therefore, have one or more of the following activities: inhibiting, interfering with, or modulating c-fms- CSF-I binding or signaling, inhibiting c-fms-IL-34 binding or signaling, reducing monocyte migration into tumors, and/or reducing the accumulation of tumor-associated macrophages (TAMs). [0007] One embodiment includes expression systems, including cell lines, for the production of c-fms receptor antigen binding proteins and methods for diagnosing and treating diseases related to human c-fms. [0008] Some of the isolated antigen-binding proteins that are described comprise (A) one or more heavy chain complementary determining regions (CDRHs) selected from the group consisting of: (i) a CDRHl selected from the group consisting of SEQ ID NOs:136-147; (ii) a CDRH2 selected from the group consisting of SEQ ID NOs: 148-164; (iii) a CDRH3 selected from the group consisting of SEQ ID NOs: 165-190; and (iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions that collectively total no more than four amino acids; (B) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of: (i) a CDRLl selected from the group consisting of SEQ ID NOs: 191-210; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs:211-224; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs:225-246; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions that collectively total no more than four amino acids; or (C) one or more heavy chain CDRHs of (A) and one or more light chain CDRLs of (B).
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