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WO 2018/185618 Al 11 October 2018 (11.10.2018) W !P O PCT

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WO 2018/185618 Al 11 October 2018 (11.10.2018) 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 2018/185618 Al 11 October 2018 (11.10.2018) W !P O PCT (51) International Patent Classification: (74) Agent: NOVARTIS AG; Lichtstrasse 35, 4056 Basel A61K 47/68 (2017.01) A61P 35/00 (2006.01) (CH). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/IB20 18/05215 1 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (22) International Filing Date: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, 28 March 2018 (28.03.2018) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (25) Filing Language: English HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (26) Publication Langi English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 62/480,972 03 April 2017 (03.04.2017) US SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: NOVARTIS AG [CH/CH]; Lichtstrasse 35, 4056 Basel (CH). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: ANTONAKOS, Brandon Peter; Novartis In GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, stitutes for BioMedical Research, Inc., 250 Massachu UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, setts Avenue, Cambridge, Massachusetts 02139 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, BIALUCHA, Carl Uli; Novartis Institutes for BioMedical, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Research, Inc., 250 Massachusetts Avenue, Cambridge, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Massachusetts 02139 (US). COLLINS, Scott; 46 Presi TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, dents Lane, Qunicy, Massachusetts 02169 (US). KNEE, KM, ML, MR, NE, SN, TD, TG). Deborah A.; Novartis Institute for Functional Genomics, Inc., dba Genomics Institute of the Novartis Research Foun Declarations under Rule 4.17: dation, 10675 John Jay Hopkins Drive, San Diego, Califor — as to applicant's entitlement to applyfor and be granted a nia 92121 (US). SHARP, Fiona Alexandra; Novartis In patent (Rule 4.1 7(H)) stitutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139 (US). (54) Title: ANTI-CDH6 ANTIBODY DRUG CONJUGATES AND ANTI-GITR ANTIBODY COMBINATIONS AND METHODS OF TREATMENT FIGURE 4 T increase following CDH6 ADC treatment in the renal tumor mouse model da s s s 300000· igG -s o-SPDB-D CDH6-sulfo-SPDB-DM4 □ * o CD4+FOXP3 CD4-!-FoxP3- CDS- (57) Abstract: The present invention relates to anti-CDH6 ADCs in combination with an anti-GITR antibody, and their uses for the treatment of cancer. [Continued on nextpage] WO 2018/185618 Al llll II II 11III II I I II II I II I II I III II I II Published: — with international search report (Art. 21(3)) — in black and white; the international application as filed contained color or greyscale and is availablefor download from PATENTSCOPE ANTI-CDH6 ANTIBODY DRUG CONJUGATES AND ANTI-GITR ANTIBODY COMBINATIONS AND METHODS OF TREATMENT FIELD [0001] The present disclosure is directed to the combination of antibody drug conjugates (ADC) in combination with anti-GITR agonist antibodies and their uses for the treatment of cancer. BACKGROUND [0002] Cadherin-6 (CDH6) is a member of the cadherin superfamily of calcium-dependent cell-cell adhesion molecules. Aside from their role in mechanical adhesion, cadherins are involved in a diverse array of cellular processes relating to tissue morphogenesis (Halbleib and Nelson Genes Dev. 2006; 20(23):3 199-3214). This superfamily is classified into classical, desmosomal, and protocadherin groups with classical cadherins subdivided into Type 1 and Type II (Sotomayor et al., Trends Cell Biol. 2014; 34(9):524-536)). CDH6 is a type II, classical cadherin, first described as K-cadherin, which was found to be preferentially expressed in fetal kidney and kidney carcinoma (Xiang et al., Cancer Res. 1994; 54(1 1):3034-3041; Paul et al., Cancer Res. 1997; 57(13):2741-2748), serous ovarian carcinoma (Kobel et al., PLoS Med. 2008 5(12):e232), as well as during normal renal development (Cho et al., Development 1998; 125(5):803-8 12; Mah et al., Dev. Biol. 2000; 223(1):38- 53). [0003] Antibody drug conjugates ("ADCs") have been used for the local delivery of cytotoxic agents in the treatment of cancer (see e.g., Lambert, Curr. Opinion In Pharmacology 2005; 5:543-549). ADCs allow targeted delivery of the drug moiety where maximum efficacy with minimal toxicity may be achieved. In addition to inducing tumor cell death, it has been demonstrated that ADCs delivering microtubule-disrupting payloads can induce a pro-inflammatory tumor microenvironment and promote anti-tumor immunity (Gerber et al., Biochem.Pharma. 2016; 102:(1- 6). [0004] Glucocorticoid-induced TNFR-related protein ("GITR") is a member of the Tumor Necrosis Factor Superfamily (TNFRSF) constitutively expressed on regulatory T cells (Tregs) and at low levels on naive and memory T cells. GITR is a bi-functional molecule capable of driving the expansion of CD8+ T effector (Teff) memory cell populations, while promoting the loss or inhibition of Tregs (Knee et al., Eur. J. Cancer 20 16; 67: 1-10). Herein, we disclose the discovery of a unique mechanism of action, wherein administration of an ADC induces GITR upregulation on Tregs, and a synergistic combination of a CDH6-targeting ADC and agonistic GITR antibody induces greater anti¬ tumor activity. SUMMARY [0005] A combination comprising: a) an anti-CDH6 antibody drag conjugate of the formula: Ab-(L-(D) )'n: or a pharmaceutically acceptable salt thereof; wherein Ab is an antibody or antigen binding fragment thereof that specifically binds to an epitope of human CDH6; L is a linker; D is a drag moiety, wherein the drag moiety is N(2')-deacetyl-N2-(4- mercapto-4-methyl- 1 - oxopentyl)-maytansine (DM4) or N(2')- deacetyl-N(2')-(3-mercapto-l-oxopropyl)-maytansine (DM1) ; m is an integer from 1 to 8; and n is an integer from 1to 10; and b) an anti-GITR agonist antibody or antigen binding fragment thereof. [0006] The combination, wherein in the antibody drag conjugate said n is 3 or 4. [0007] The combination, wherein in said antibody drag conjugate said antibody or antigen binding fragment thereof comprises: (i) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:224, (b) a LCDR2 of SEQ ID NO:225, (c) a LCDR3 of SEQ ID NO:226; and a heavy chain variable region that comprises: (d) a HCDRl of SEQ ID NO: 227, (e) a HCDR2 of SEQ ID NO: 228, and (f) a HCDR3 of SEQ ID NO:229; (ii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:2 10, (b) a LCDR2 of SEQ ID NO:21 1, (c) a LCDR3 of SEQ ID NO:212; and a heavy chain variable region that comprises: (d) a HCDRl of SEQ ID NO:213, (e) a HCDR2 of SEQ ID NO: 214, and (f) a HCDR3 of SEQ ID NO:215; (iii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:266, (b) a LCDR2 of SEQ ID NO:267, (c) a LCDR3 of SEQ ID NO:268; and a heavy chain variable region that comprises: (d) a HCDRl of SEQ ID NO: 269, (e) a HCDR2 of SEQ ID NO:270, and (f) a HCDR3 of SEQ ID NO: 27 1; (iv) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:308, (b) a LCDR2 of SEQ ID NO:309, (c) a LCDR3 of SEQ ID NO:3 10; and a heavy chain variable region that comprises: (d) a HCDRl of SEQ ID NO:3 11, (e) a HCDR2 of SEQ ID NO:3 12, and (f) a HCDR3 of SEQ ID NO:3 13; (v) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO: 14, (b) a LCDR2 of SEQ ID NO: 15, (c) a LCDR3 of SEQ ID NO: 16; and a heavy chain variable region that comprises: (d) a HCDRI of SEQ ID NO: 17, (e) a HCDR2 of SEQ ID NO: 18, and (f) a HCDR3 of SEQ ID NO: 19; (vi) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:28, (b) a LCDR2 of SEQ ID NO:29, (c) a LCDR3 of SEQ ID NO:30; and a heavy chain variable region that comprises: (d) a HCDRI of SEQ ID NO:3 1, (e) a HCDR2 of SEQ ID NO:32, and (f) a HCDR3 of SEQ ID NO:33; (vii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:42, (b) a LCDR2 of SEQ ID NO:43, (c) a LCDR3 of SEQ ID NO:44; and a heavy chain variable region that comprises: (d) a HCDRI of SEQ ID NO:45, (e) a HCDR2 of SEQ ID NO:46, and (f) a HCDR3 of SEQ ID NO:47; (viii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:56, (b) a LCDR2 of SEQ ID NO:57, (c) a LCDR3 of SEQ ID NO:58; and a heavy chain variable region that comprises: (d) a HCDRI of SEQ ID NO:59, (e) a HCDR2 of SEQ ID NO:60, and (f) a HCDR3 of SEQ ID NO:61; (ix) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO:70, (b) a LCDR2 of SEQ ID NO:71, (c) a LCDR3 of SEQ ID NO:72; and a heavy chain variable region that comprises: (d) a HCDRI of SEQ ID NO:73, (e) a HCDR2 of SEQ ID NO:74, and (f) a HCDR3 of SEQ ID NO:75; (x) a light chain variable
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