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WO 2018/107109 Al 14 June 2018 (14.06.2018) W !P O PCT

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WO 2018/107109 Al 14 June 2018 (14.06.2018) W !P O PCT (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 2018/107109 Al 14 June 2018 (14.06.2018) W !P O PCT (51) International Patent Classification: (74) Agent: MEIGS, Julie Broadus et al; Womble Bond A61K 39/395 (2006.01) C07K 14/705 (2006.01) Dickinson (US) LLP, P.O. Box 7037, Atlanta, Georgia A61K 47/48 (2006.01) C07K 16/28 (2006.01) 30357-0037 (US). A61P 35/00 (2006.01) C07K 16/30 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US20 17/065445 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 0 8 December 2017 (08.12.2017) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (25) Filing Language: English KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (30) Priority Data: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/432,050 0 9 December 20 16 (09. 12. 20 16) U S TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/593,901 02 December 20 17 (02 .12 .20 17) U S (84) Designated States (unless otherwise indicated, for every (71) Applicant: ABBVIE STEMCENTRX LLC [US/US]; 1 kind of regional protection available): ARIPO (BW, GH, North Waukegan Road, North Chicago, Illinois 60064 (US). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 3000 MONTEREY (72) Inventors: WILLIAMS, Samuel A.; TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, STREET, SAN MATEO, California 94403 (US). FONG, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Sarah; 4432 39TH AVENUE, OAKLAND, California MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 94619 (US). 300 SANTA ROSA AVENUE, LIU, David; TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, APT. 1, SAN FRANCISCO, California 941 12 (US). KM, ML, MR, NE, SN, TD, TG). (54) Title: NOVEL ANTI-KREMEN2 ANTIBODIES AND METHODS O F USE (57) Abstract: Provided are novel anti-KREMEN2 antibodies and antibody drug conjugates, and methods of using such anti-KREMEN2 antibodies and antibody Anti-KREMEN2 ANTIBODY DRUG CONJUGATES EFFECTIVELY DEPLETE CANCER STEM CELLS drug conjugates to treat cancer. LU460 CSC FREQUENCY ION f Υ//Λ 0 © o 0 0 FIG. 17 o [Continued on nextpage] WO 2018/107109 Al llll II II 11III II I 1 1 II III I II 11III II I II Declarations under Rule 4.17: — as to applicant's entitlement to applyfor and be granted a patent (Rule 4.1 7(H)) — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(in)) 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)) — with sequence listing part of description (Rule 5.2(a)) NOVEL ANTI-KREMEN2 ANTIBODIES AND METHODS OF USE CROSS REFERENCED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62/432,050 filed on December 9, 2016 and U.S. Provisional Application No. 62/593,901 filed on December 2, 2017, each of which is incorporated herein by reference in its entirety. SEQUENCE LISTING This application contains a sequence listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on December 7, 2017, is named S69697_1440WO_SC7801WOOl_ST25.txt and is 139 KB (143,277 bytes) in size. FIELD OF THE INVENTION This application generally relates to anti-KREMEN2 antibodies or immunoreactive fragments or derivatives thereof, including antibody drug conjugates, and compositions comprising the same for the treatment, diagnosis or prophylaxis of cancer and any recurrence or metastasis thereof. Selected embodiments of the invention provide for the use of such anti-KREMEN2 antibodies or antibody drug conjugates for the treatment of cancer comprising a reduction in tumorigenic cell frequency. BACKGROUND OF THE INVENTION Differentiation and proliferation of stem cells and progenitor cells are normal ongoing processes that act in concert to support tissue growth during organogenesis, cell repair and cell replacement. The system is tightly regulated to ensure that only appropriate signals are generated based on the needs of the organism. Cell proliferation and differentiation normally occur only as necessary for the replacement of damaged or dying cells or for growth. However, disruption of these processes can be triggered by many factors including the under- or overabundance of various signaling chemicals, the presence of altered microenvironments, genetic mutations or a combination thereof. Disruption of normal cellular proliferation and/or differentiation can lead to various disorders including proliferative diseases such as cancer. Conventional therapeutic treatments for cancer include chemotherapy, radiotherapy and immunotherapy. Often these treatments are ineffective and surgical resection may not provide a viable clinical alternative. Limitations in the current standard of care are particularly evident in those cases where patients undergo first line treatments and subsequently relapse. In such cases refractory tumors, often aggressive and incurable, frequently arise. The overall survival rates for many tumors have remained largely unchanged over the years due, at least in part, to the failure of existing therapies to prevent relapse, tumor recurrence and metastasis. There remains therefore a great need to develop more targeted and potent therapies for proliferative disorders. The current invention addresses this need. SUMMARY OF THE INVENTION In a broad aspect the present invention provides novel antibodies, and corresponding antibody drug or diagnostic conjugates (ADCs), or compositions thereof, which specifically bind to human KREMEN2 determinants. In certain embodiments the KREMEN2 determinant is a KREMEN2 protein expressed on tumor cells while in other embodiments the KREMEN2 determinant is expressed on tumor initiating cells. In other embodiments the antibodies of the invention bind to a KREMEN2 protein and compete for binding with an antibody that binds to an epitope on human KREMEN2 protein. In selected embodiments the invention comprises an antibody that comprises or competes for binding with an isolated antibody that binds to a cell expressing human KREMEN2 having SEQ ID NO: 1, wherein the isolated antibody comprises: (1) a light chain variable region (VL) of SEQ ID NO: 2 1 and a heavy chain variable region (VH) of SEQ ID NO: 23; or (2) a VL of SEQ ID NO: 25 and a VH of SEQ ID NO: 27; or (3) a VL of SEQ ID NO: 29 and a VH of SEQ ID NO: 31; or (4) a VL of SEQ ID NO: 33 and a VH of SEQ ID NO: 35; or (5) a VL of SEQ ID NO: 37 and a VH of SEQ ID NO: 39; or (6) a VL of SEQ ID NO: 4 1 and a VH of SEQ ID NO: 43; or (7) a VL of SEQ ID NO: 45 and a VH of SEQ ID NO: 47; or (8) a VL of SEQ ID NO: 49 and a VH of SEQ ID NO: 51; or (9) a VL of SEQ ID NO: 53 and a VH of SEQ ID NO: 55; or (10) a VL of SEQ ID NO: 57 and a VH of SEQ ID NO: 59; or ( 11) a VL of SEQ ID NO: 6 1 and a VH of SEQ ID NO: 63; or (12) a VL of SEQ ID NO: 65 and a VH of SEQ ID NO: 67; or (13) a VL of SEQ ID NO: 69 and a VH of SEQ ID NO: 71; or (14) a VL of SEQ ID NO: 73 and a VH of SEQ ID NO: 75; or (15) a VL of SEQ ID NO: 77 and a VH of SEQ ID NO: 79; or (16) a VL of SEQ ID NO: 49 and a VH of SEQ ID NO: 81. In a further aspect, the invention comprises an antibody that binds to KREMEN2 comprising a light chain variable region and a heavy chain variable region, wherein the light chain variable region has three CDRs of a light chain variable region set forth as SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 69, SEQ ID NO: 73 and SEQ ID NO: 77 and the heavy chain variable region has three CDRs of a heavy chain variable region set forth as SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO:59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 71, SEQ ID NO: 75, SEQ ID NO: 77 and SEQ ID NO: 81.
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