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WO 2016/070089 A2 6 May 2016 (06.05.2016) W P O P C T

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WO 2016/070089 A2 6 May 2016 (06.05.2016) W P O P C T (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 WO 2016/070089 A2 6 May 2016 (06.05.2016) W P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07K 16/28 (2006.01) A61K 31/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 47/48 (2006.01) A61P 35/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/058389 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 30 October 2015 (30.10.201 5) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/073,824 31 October 2014 (3 1. 10.2014) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: ABBVIE BIOTHERAPEUTICS INC. TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, [US/US]; 1500 Seaport Boulevard, Redwood City, Califor TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, nia 94063 (US). 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, (72) Inventors: GISH, Kurt C ; 37 Artuna Avenue, Piedmont, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, California 946 11 (US). KIM, Han K.; 2743 Delaware GW, KM, ML, MR, NE, SN, TD, TG). Street, Redwood City, California 94061 (US). NAUMOVSKI, Louie; 570 Jay Street, Los Altos, Califor Published: nia 94022 (US). — without international search report and to be republished (74) Agents: DECHERT LLP et al; Suite 700, 2440 W. El upon receipt of that report (Rule 48.2(g)) Camino Real, Mountain View, California 94040-1499 — with sequence listing part of description (Rule 5.2(a)) (US). (54) Title: ANTI-CSl ANTIBODIES AND ANTIBODY DRUG CONJUGATES (57) Abstract: The present disclosure provides antibodies and antibody drug conjugates that bind human CSl and their uses to treat subjects diagnosed with a plasma cell neoplasm, for example, multiple myeloma. ANTI-CS1 ANTIBODIES AND ANTIBODY DRUG CONJUGATES 1. CROSS REFERENCE TO RELATED APPLICATIONS [000 ] This application claims the benefit under 35 U.S.C. § (e) of U. S, Provisional Application no, 62/073,824, filed October 31, 2014, the contents of which is incorporated herein in its entirety by reference thereto. 2, REFERENCE TO SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on October 22, 20 15, is named 381493-838US(136841)_SL.txt and is 77,289 bytes in size. 3, FIELD [0003] This present application pertains to, among other things, new anti-CSl antibodies that bind an epitope different from known anti-CSl antibodies, antibody drug conjugates ("ADCs") comprising the new anti-CSl antibodies, compositions including the new antibodies and ADCs, methods of making the new antibodies and ADCs, and methods of using the new antibodies and ADCs to modulate biological processes and treat diseases. 4, BACKGROUND [0004] Multiple myeloma ("MM") is an incurable malignancy arising from postgerminal mature B cells, characterized by an excess of monotypic plasma cells in the bone marrow and elevated levels of monoclonal immunoglobulins in the serum and/or urine (Lonial et a!,, 2012, J Clin Oncol 30:1953- 1959). Common clinical sequelae include lytic bone lesions, fractures, myeiosuppression, and renal failure. In the United States, the estimated annual diagnosed incidence is 20,000 (Lonial el a!,, 20 2, J Clin Oncol 30: 1953-1959). MM accounts for 15% of all hematologic malignancies and 2% of all malignancies (Lonial et i , 2012, J Clin Oncol 30:1953-1959). Advances in high-dose chemotherapy and stem cell transplantation have improved overall survival (OS) and event-free disease periods in MM (Lonial et a ., 2012, J Clin Oncol 30: 3953-1959), although relapses are inevitable. Newer therapeutic agents, such as proteasome inhibitors (currently approved: Velcade© (boriezomib), Kyprolis® (carfilzomib)), and the immunomodulatory drugs thalidomide, Reviimid® (lenalidomide), and Pomalyst® (poma!idomide) have demonstrated clinical benefit in patients with newly diagnosed, relapsed or refractory disease (Loniai et al, 2012. J Clin Oncol 30:1953-1959), Despite these therapeutic advances, long-term control of relapsed or refractory MM remains an unmet medical need for most MM patients. Progressive disease that is resistant to both immunomodulatory drugs (IMiDs) and proteasome inhibitors is associated with a particularly poor prognosis (Loniai et al, 2012, J Clin Onco 30:1953-1959) As such, there remains an important need for additional novel therapies to augment existing first-generation agents and continue to improve patient outcome. [00051 CS1 (also known as SLAMF7, CRACC, 19A, APEX-1, and FOAP12) is a ceil surface glycoprotein that has emerged as a new target antigen for therapeutic antibodies in multiple myeloma (MM) (Loniai etal, 2012, J Clin Oncol 30:1953-1959). Elotuzumab is a humanized monoclonal immunoglobulin G 1 antibody targeting CS1 (see, e.g., PCX publications WO 2004/100898, WO 2005/102387, WO 2008/019376, and WO 2008/019378; see also U.S. Patent Nos. 8,088,898, 8,133,981, ,008 ,450, 8,445,646, 8,349,330, 8,461,306, 8,444,980, 8,436,146, 7,709,610, 8,632,772, and 7,842,293). Elotuzumab has shown encouraging antimyeloma activity in preclinical studies when used alone or in combination with other approved agents. For example, elotuzumab and lenalidomide have certain complementary mechanisms of action. Lenalidomide has been shown to increase the number and anti-MM cytotoxic activity of NK cells (Loniai et al, 2012, J Clin Oncol 30:1953-1959), Elotuzumab acts primarily through NK cell-rnediated ADCC (Loniai et al, 20 1 , J C!in Oncol 30: 953- 959). A Phase III clinical trial, ELOQUENT-2, evaluated the efficacy and safety of elotuzumab in combination with lenalidomide and dexamethasone, as compared with lenalidomide and dexamethasone alone, in patients with relapsed or refractory multiple myeloma. In patients with relapsed or refractory multiple myeloma, the addition of elotuzumab to lenalidomide and dexamethasone, as compared with lenalidomide and dexamethasone as control therapy, improved progression-free survival and the overall response rate, showing that direct activation and engagement of the innate immune system selectively to target myeloma cells can provide clinically meaningful and statistically significant improvements in treatment outcomes. Specifically, Kaplan-Meier curves for progression-free survival showed early and increasing separation between the two groups oyer time. Patients receiving elotuzumab had a relative reduction of 30% in the risk of disease progression or death as compared with the control group (Loniai et al, 2015, N Engl J Med , 373:621-631). [0006] Although the results with elotuzumab are promising, there remains a need to identify novel therapies that do not exert their anti-myeloma effect primarily via NK cell-mediated ADCC (Zonder, 2012, Blood, 120:552-559), n part because MM patients with advanced disease often have an impaired immune system (Pratt, 2007, Br J Haematol 138:563-579), Therapies that work effectively with an impaired immune system would be desirable. 5. SUMMARY [0007] n one aspect, the present disclosure provides new antibodies, and/or binding fragments, that specifically bind human CSl ("HuCS I"; SEQ ID NO: I) at epitopes different from the epitopes bound by anti-CSl antibodies reported in the literature, and in particular antibodies LucX (and its humanized version, PDL241), elotuzuraab and Luc34.3.8 (see, e.g., PCX publications WO 2004/100898, WO 2005/102387, and Woo, el 20 , Arthritis Res Ther 5(6):R207). O e of the new antibodies binds a unique epitope. This antibody exhibits superior anti-proliferation properties in vivo. Unlike elotuzumab, all of the new antibodies and binding fragments described herein cross react with cynomolgus CSl ("CrnCSl"; SEQ ID :3), This property is advantageous in that it permits safety testing n cynomolgus monkeys. [0008] The new antibodies and/or binding fragments generally comprise a variable heavy (V H) chain having three complementarity determining regions ("CDRs") referred to herein (in N→C order) as V H CDR#1, V h CDR#2, and V H CDR#3, and a variable light (V ) chain having three complementarity determining regions referred to herein (in N-→C order) as V CDR#1, V CDR 2 and V CDR#3 The amino acid sequences of the V and V regions of the heavy and light chains of a number of exemplary anti-CSl antibodies have been determined, and their CDRs identified. With the exception of antibody Mu27 , the sequences of the respective heavy and light chain CDRs of exemplary anti-CSl antibodies disclosed herein exhibit a high degree of similarity. Accordingly, anti-CSl antibodies comprising any combination of heavy chain CDRs and any combination of light chain CDRs, as well as any combination of V and chains disclosed herein are contemplated.
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