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`Organization
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`International Bureau
`
`=z
`Soe=\
`
`AMCTACOMAATAAA
`
`(10) International Publication Number
`WO 2016/024195 Al
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`=
`
`(43) International Publication Date
`18 February 2016 (18.02.2016)
`
`WIPOI|PCT
`
`(51) International Patent Classification:
`CO07K 16/28 (2006.01)
`A61P 35/00 (2006.01)
`A61K 39/395 (2006.01)
`A61K 31/00 (2006.01)
`
`(21) International Application Number:
`
`PCT/IB2015/056032
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`7 August 2015 (07.08.2015)
`
`English
`
`English
`
`(30) Priority Data:
`62/036,382
`
`12 August 2014 (12.08.2014)
`
`US
`
`(for all designated States except US): NO-
`(71) Applicant
`VARTIS AG [CH/CH]; Lichtstrasse 35, 4056 Basel (CH).
`
`(71) Applicant: DURR, Clemens [DE/CH]; Novartis Pharma
`AG,Postfash, 4002 Basel (CH).
`
`Inventors; and
`(72)
`(71) Applicants
`(for US only): BIALUCHA, Carl Uli
`[DE/US]; Novartis Institutes for BioMedical Research,
`Inc., 250 Massachusetts Avenue, Cambridge, Massachu-
`setts 02139 (US). COLLINS, Scott [GB/US]; Novartis In-
`stitutes for BioMedical Research, Inc., 250 Massachusetts
`Avenue, Cambridge, Massachusetts 02139 (US). HU,
`Tiancen [US/US]; Novartis Institutes for BioMedical Re-
`search, Inc., 250 Massachusetts Avenue, Cambridge, Mas-
`sachusetts
`02139
`(US).
`JANATPOUR, Mary
`Jo
`[US/US]; Novartis Institutes for BioMedical Research,
`Inc., 5300 Chiron Way, Emeryville, California 94608
`(US). MEYER, Matthew John [US/US]; Novartis Insti-
`tutes for BioMedical Research, Inc., 250 Massachusetts
`Avenue, Cambridge, Massachusetts 02319 (US).
`
`(74) Agent: NOVARTIS AG; Lichtstrasse 35, 4056 Basel
`(CH).
`
`(81)
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, 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,IN,IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`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,
`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.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`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,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, KM,ML, MR,NE, SN, TD, TG).
`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 sequencelisting part ofdescription (Rule 5.2(a))
`
`(54) Title: ANTI-CDH6 ANTIBODY DRUG CONJUGATES
`
`(57) Abstract: The present invention relates to anti-CDH6antibodies, antibody fragments, antibody drug conjugates, and their uses
`for the treatment of cancer.
`
`
`
`
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`ANTL-CDH6 ANTIBODY DRUG CONJUGATES
`
`FIELD OF THE INVENTION
`
`[0001]
`
`The present disclosure is directed to anti-CDH6 antibodies, antibody fragments,
`
`antibody drug conjugates, and their uses for the treatment of cancer.
`
`BACKGROUND OF THE INVENTION
`
`[0002]
`
`Cadherins are a family of cell adhesion molecules involved in cell-cell contact. There
`
`are more than 30 cadherin molecules in the family which consists of subclasses with individual
`
`binding specificities. There are well studied classic cadherins such as epithelial (E) cadherin, neural
`
`(N) cadherin and placental (P) cadherin which play key roles in the development and maintenance of
`
`tissues such as the epithelium. The cadherin family has also been classified by their amino acid
`
`similarities, which separate the cadherins into two groups, type I and type II. Thenthere are tissue
`
`specific cadherins such as cadherin-6 (CDH6).
`
`[0003]
`
`CDH6wasfirst cloned and characterized in 1995 (Shimoyama etal., Cancer Res.
`
`1995: 55 (10)2206-2211). The CDH6 cDNAisolated by Shimoyama was 4315 nucleotides and coded
`
`for a cadherin protein of 790 amino acids and exhibited 97% homology with rat K-cadherin
`
`(Shimoyama, supra). CDH6is a type II cadherin with five extracellular cadherin repeats, a
`
`transmembrane domain and a cytoplasmic domain. In probing for normal tissue expression, CDH6
`
`wasdetected in brain, cerebellum and kidney, with weaker expression in the lung, pancreas and gastric
`
`mucosa. In the nervous system, CDH6 was found to demarcate the auditory and somatosensory
`
`systems (Inoueet al., Mol. Cell Neuro. 2008: (39) 95-104). It was demonstrated that CDH6 is
`
`expressed by a subsetof retinal ganglion cells (RGCs) in the eye responsible for such vision qualities
`
`as brightness, direction of motion or edges (Osterhoutet al., Neuron 2011: 71(4)632-639).
`
`Inthe
`
`CDH6knockout mouse, the absence of CDH6 causeloss of axon targeting. The CDH6 mutant axons
`
`elongated properly and were appropriately guidedto their targets, but then grew through andpast their
`
`connections (Osterhout, supra). In another study, CDH6 knockout mice demonstrated defects in
`
`vocalization (Nakagawaeta la., PLOS 2012: 7(11) e49233).
`
`[0004]
`
`Turning to its expression in cancer, the CDH6 cDNA wascloned from a
`
`hepatocellular carcinoma cell line, which was an early indication it may be involvedin this type of
`
`cancer (Shimoyama, supra). The early work found CDH6 expression in several hepatoma lines, but
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`no expression in normal liver. In later work, a group analyzed 216 patients with renal cell carcinoma
`
`and found that CDH6 expression correlated with this type of cancer (Paul etal., J Urology 2004 (171):
`
`97-101). Shimazui foundthat renal cell carcinoma patients who expressed CDH6 and lacked E-
`
`cadherin expression had a poor prognosis (Shimazuiet al., Clin. Cancer Res. 1998 (4): 2419-2424). It
`
`wasalso discovered that CDH6 was a TGF-Btarget and playsa role in thyroid cancer (Sancisiet al.,
`
`PLoS One 2013; 8(9): e75489). Lastly, CDH6 was shownto be a biomarker for ovarian cancer
`
`(Kobelet al., PLoS One 2008 5(12): e232).
`
`[0005]
`
`Antibody drug conjugates (“ADCs”) have been usedfor the local delivery of
`
`cytotoxic agents in the treatment of cancer(see e.g., Lambert, Curr. Opinion In Pharmacology 5:543-
`
`549, 2005). ADCs allow targeted delivery of the drug moiety where maximum efficacy with minimal
`
`toxicity may be achieved. As more ADCs show promisingclinical results, there is an increased need
`
`to develop new therapeutics for cancer therapy.
`
`SUMMARYOF THE INVENTION
`
`[0006]
`
`An antibody drug conjugate of the formula:
`
`Ab-(L-D)m)n
`
`or a pharmaceutically acceptable salt thereof; wherein
`
`Abis an antibody or antigen binding fragmentthereof that specifically binds to an epitope of human
`
`CDH6;
`
`Lisalinker;
`
`D is a drug moiety;
`
`m is an integer from | to 8; and
`
`nis an integer from | to 10.
`
`[0007]
`
`The antibody drug conjugate according of any of the preceding embodiments, wherein
`
`said nis 3 or 4.
`
`[0008]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein said
`
`antibody or antigen binding fragment thereof specifically binds the extracellular domain of CDH6
`
`(SEQ ID NO:4).
`
`[0009]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein said
`
`antibody or antigen binding fragmentspecifically binds to an epitope of human CDH6at SEQ ID
`
`NO:534.
`
`[0010]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein said
`
`antibody or antigen binding fragment thereof comprises:
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`(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 HCDR1 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:210, (b) a LCDR2 of SEQ ID NO:211, (c) a LCDR3 of SEQ ID NO:212; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:213, (ce) 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 HCDR1 of SEQ ID NO: 269, (e) a HCDR2 of SEQ
`
`ID NO:270, and (f) a HCDR3 of SEQ ID NO: 271;
`
`(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:310; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:311, (e) aHCDR2 of SEQ
`
`ID NO:312, and (f) a HCDR3 of SEQ ID NO:313;
`
`(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 HCDR1 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 HCDR1 of SEQ ID NO:31, (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 HCDR1 of SEQ ID NO:45, (e) a HCDR2 of SEQ ID
`
`NO:46, and (f) a HCDR3 of SEQ ID NO:47;
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`(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 HCDR1 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 HCDR1 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 region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:84, (b) a LCDR2 of SEQ ID NO:85, (c) a LCDR3 of SEQ ID NO:86; and a
`
`heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:87, (e) a HCDR2 of SEQ ID
`
`NO: 88, and (f) a HCDR3 of SEQ ID NO: 89;
`
`(xi) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:98, (b) a LCDR2 of SEQ ID NO:99, (c) a LCDR3 of SEQ ID NO:100; and a
`
`heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:101, (ce) a HCDR2 of SEQ
`
`ID NO:102, and (f) a HCDR3 of SEQ ID NO: 103;
`
`(xii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:112, (b) a LCDR2 of SEQ ID NO:113, (c) a LCDR3 of SEQ ID NO:114; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:115, (ce) a HCDR2 of SEQ
`
`ID NO:116, and (f) a HCDR3 of SEQ ID NO:117;
`
`(xiii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:126, (b) a LCDR2 of SEQ ID NO:127, (c) a LCDR3 of SEQ ID NO:128; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:129, (ec) a HCDR2 of SEQ
`
`ID NO: 130, and (f) a HCDR3 of SEQ ID NO:131,
`
`(xiv) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:140, (b) a LCDR2 of SEQ ID NO:141, (c) a LCDR3 of SEQ ID NO:142; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:143, (ce) a HCDR2 of SEQ
`
`ID NO: 144, and (f) a HCDR3 of SEQ ID NO: 145;
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`(xv) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:154, (b) a LCDR2 of SEQ ID NO:155, (c) a LCDR3 of SEQ ID NO:156; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:157, (e) aHCDR2 of SEQ
`
`ID NO:158, and (f) a HCDR3 of SEQ ID NO:159;
`
`(xvi) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO: 168, (b) a LCDR2 of SEQ ID NO:169, (c) a LCDR3 of SEQ ID NO:170; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:171, (e¢) aHCDR2 of SEQ
`
`ID NO:172, and (f) a HCDR3 of SEQ ID NO:173;
`
`(xvii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:182, (b) a LCDR2 of SEQ ID NO:183, (c) a LCDR3 of SEQ ID NO:184; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:185, (ce) aHCDR2 of SEQ
`
`ID NO: 186, and (f) a HCDR3 of SEQ ID NO:187,
`
`(xviii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:196, (b) a LCDR2 of SEQ ID NO:197, (c) a LCDR3 of SEQ ID NO:198; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:199, (ce) aHCDR2 of SEQ
`
`ID NO:200, and (f) a HCDR3 of SEQ ID NO:201;
`
`(xix) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:238,(b) a LCDR2 of SEQ ID NO:239, (c) a LCDR3 of SEQ ID NO:240; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:241, (ec) a HCDR2 of SEQ
`
`ID NO:242, and (f) a HCDR3 of SEQ ID NO:243;
`
`(xx) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:252, (b) a LCDR2 of SEQ ID NO:253, (c) a LCDR3 of SEQ ID NO:254; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:255, (ce) a HCDR2 of SEQ
`
`ID NO:256, and (f) a HCDR3 of SEQ ID NO:257,
`
`(xxi) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:280, (b) a LCDR2 of SEQ ID NO:281, (c) a LCDR3 of SEQ ID NO:282; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:283, (ce) a HCDR2 of SEQ
`
`ID NO:284, and (f) a HCDR3 of SEQ ID NO:285;
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`(xxii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:294,(b) a LCDR2 of SEQ ID NO:295, (c) a LCDR3 of SEQ ID NO:296; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:297, (ce) a HCDR2 of SEQ
`
`ID NO:298, and (f) a HCDR3 of SEQ ID NO:299; or
`
`(xxiii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:322, (b) a LCDR2 of SEQ ID NO:323, (c) a LCDR3 of SEQ ID NO:324; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:325, (ce) a HCDR2 of SEQ
`
`ID NO:326, and (f) a HCDR3 of SEQ ID NO:327.
`
`[0011]
`
`The antibody drug conjugate of any of the preceding embodiments, in whichatleast
`
`one amino acid within a CDRis substituted by a corresponding residue of a corresponding CDR of
`
`another anti-CDH6 antibody in Table 5 or6.
`
`[0012]
`
`The antibody drug conjugate of any of the preceding embodiments, in which one or
`
`two aminoacids within a CDR have been modified, deleted or substituted.
`
`[0013]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein said
`
`antibody or antigen binding fragment thereof comprises:
`
`(i) a heavy chain variable region (vH) that comprises SEQ ID NO: 230, anda light chain variable
`
`region (vL) that comprises SEQ ID NO:231;
`
`(ii) a heavy chain variable region (vH) that comprises SEQ ID NO: 216, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:217;
`
`(iii) a heavy chain variable region (vH) that comprises SEQ ID NO: 272, anda light chain variable
`
`region (vL) that comprises SEQ ID NO:273;
`
`(iv) a heavy chain variable region (vH) that comprises SEQ ID NO:314, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:315;
`
`(v) a heavy chain variable region (vH) that comprises SEQ ID NO:20, and a light chain variable region
`
`(vL) that comprises SEQ ID NO:21;
`
`(vi) a heavy chain variable region (vH) that comprises SEQ ID NO: 34, andalight chain variable
`
`region (vL) that comprises SEQ ID NO:35;
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`(vii) a heavy chain variable region (vH) that comprises SEQ ID NO:48, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:49;
`
`(viii) a heavy chain variable region (vH) that comprises SEQ ID NO:62, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:63;
`
`(ix) a heavy chain variable region (vH) that comprises SEQ ID NO:76, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:77;
`
`(x) a heavy chain variable region (vH) that comprises SEQ ID NO:90, and a light chain variable region
`
`(vL) that comprises SEQ ID NO:91;
`
`(xi) a heavy chain variable region (vH) that comprises SEQ ID NO: 104, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:105;
`
`(xii) a heavy chain variable region (vH) that comprises SEQ ID NO: 118, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:119;
`
`(xiii) a heavy chain variable region (vH) that comprises SEQ ID NO: 132, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:133;
`
`(xiv) a heavy chain variable region (vH) that comprises SEQ ID NO: 146, and a light chain variable
`
`region (vL) that comprises SEQ ID NO: 147;
`
`(xv) a heavy chain variable region (vH) that comprises SEQ ID NO:160, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:161;
`
`(xvi) a heavy chain variable region (vH) that comprises SEQ ID NO: 174, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:175;
`
`(xvii) a heavy chain variable region (vH) that comprises SEQ ID NO: 188, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:189;
`
`(xviii) a heavy chain variable region (vH) that comprises SEQ ID NO: 202, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:203;
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`(xix) a heavy chain variable region (vH) that comprises SEQ ID NO: 244,and a light chain variable
`
`region (vL) that comprises SEQ ID NO:245;
`
`(xx) a heavy chain variable region (vH) that comprises SEQ ID NO:258, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:259;
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`(xxi) a heavy chain variable region (vH) that comprises SEQ ID NO:286,and a light chain variable
`
`region (vL) that comprises SEQ ID NO:287;
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`(xxii) a heavy chain variable region (vH) that comprises SEQ ID NO:300, and a light chain variable
`
`region (vL) that comprises SEQ ID NO:301; or
`
`(xxiii) a heavy chain variable region (vH) that comprises SEQ ID NO:328, anda light chain variable
`
`region (vL) that comprises SEQ ID NO:329.
`
`[0014]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein said
`
`antibody or antigen binding fragment thereof comprises:
`
`(i) a heavy chain that comprises SEQ ID NO: 234, and a light chain that comprises SEQ ID NO:235;
`
`(ii) a heavy chain that comprises SEQ ID NO: 220, and a light chain that comprises SEQ ID NO:221;
`
`(iii) a heavy chain that comprises SEQ ID NO: 276, and a light chain that comprises SEQ ID NO:277;
`
`(iv) a heavy chain that comprises SEQ ID NO:318, and a light chain that comprises SEQ ID NO:319;
`
`(v) a heavy chain that comprises SEQ ID NO:24, and a light chain that comprises SEQ ID NO:25;
`
`(vi) a heavy chain that comprises SEQ ID NO: 38, and a light chain that comprises SEQ ID NO:39;
`
`(vii) a heavy chain that comprises SEQ ID NO:52, and a light chain that comprises SEQ ID NO:53;
`
`(viii) a heavy chain that comprises SEQ ID NO:66,anda light chain that comprises SEQ ID NO:67;
`
`(ix) a heavy chain that comprises SEQ ID NO:80, and a light chain that comprises SEQ ID NO:81;
`
`(x) a heavy chain that comprises SEQ ID NO:94, and a light chain that comprises SEQ ID NO:95;
`
`(xi) a heavy chain that comprises SEQ ID NO:108,and a light chain that comprises SEQ ID NO:109;
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`(xii) a heavy chain that comprises SEQ ID NO: 122,and a light chain that comprises SEQ ID NO:123;
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`(xiii) a heavy chain that comprises SEQ ID NO:136,and a light chain that comprises SEQ ID NO:137;
`
`(xiv) a heavy chain that comprises SEQ ID NO:150, and a light chain that comprises SEQ ID NO:151;
`
`(xv) a heavy chain that comprises SEQ ID NO: 164, and a light chain that comprises SEQ ID NO: 165;
`
`(xvi) a heavy chain that comprises SEQ ID NO:178, and a light chain that comprises SEQ ID NO:179;
`
`(xvii) a heavy chain that comprises SEQ ID NO:192, and a light chain that comprises SEQ ID
`
`NO:193;
`
`(xviii) a heavy chain that comprises SEQ ID NO:206, and a light chain that comprises SEQ ID
`
`NO:207;
`
`(xix) a heavy chain that comprises SEQ ID NO:248,and a light chain that comprises SEQ ID NO:249;
`
`(xx) a heavy chain that comprises SEQ ID NO:262, and a light chain that comprises SEQ ID NO:263;
`
`(xxi) a heavy chain that comprises SEQ ID NO:290, and a light chain that comprises SEQ ID NO:291;
`
`(xxii) a heavy chain that comprises SEQ ID NO:304, and a light chain that comprises SEQ ID
`
`NO:305; or
`
`(xxiii) a heavy chain that comprises SEQ ID NO:332, and a light chain that comprises SEQ ID
`
`NO:333.
`
`[0015]
`
`The antibody drug conjugate of any of the preceding embodimentsthatretains at least
`
`90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identity over either the variable light or variable heavy
`
`region.
`
`[0016]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein the
`
`antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered
`
`antibody, a human antibody, a single chain antibody(scFv) or an antibody fragment.
`
`[0017]
`
`The antibody drug conjugate according to any of the preceding embodiments, wherein
`
`said linker (L) is selected from the group consisting of a cleavable linker, a non-cleavable linker, a
`
`hydrophilic linker, a procharged linker and a dicarboxylic acid based linker.
`
`[0018]
`
`The antibody drug conjugate according to any of the preceding embodiments, wherein
`
`the linker is derived from a cross-linking reagent selected from the group consisting of: N-
`
`succinimidyl-4-(2-pyridyldithio)2-sulfo-butanoate (sulfo-SPDB), N-succinimidy1-3-(2-
`
`pytidyldithio)propionate (SPDP), N-succinimidy] 4-(2-pyridyldithio)pentanoate (SPP), N-
`
`succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidy] iodoacetate (SIA), N-
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`succinimidyl(4-iodoacety]l)aminobenzoate (SIAB), maleimide PEG NHS, N-succinimidy] 4-
`
`(maleimidomethyl) cyclohexanecarboxylate (SMCC), N- sulfosuccinimidy! 4-(maleimidomethyl)
`
`cyclohexanecarboxylate (sulfo-SMCC)or 2,5-dioxopyrrolidin-1-y1 17-(2,5-dioxo-2,5-dihydro-1H-
`
`pytrol-1-yl)-5,8,11,14-tetraoxo-4,7, 10,13-tetraazaheptadecan-1l-oate (CX1-1).
`
`[0019]
`
`The antibody drug conjugate according to any of the preceding embodiments, wherein
`
`said linker is derived from N-succinimidy1-4-(2-pyridyldithio)2-sulfo-butanoate (sulfo-SPDB).
`
`[0020]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein said drug
`
`moiety (D) is selected from a group consisting of: a maytansinoid, a V-ATPase inhibitor, a pro-
`
`apoptotic agent, a Bcl2 inhibitor, an MCL1 inhibitor, a HSP90 inhibitor, an IAP inhibitor, an mTor
`
`inhibitor, a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a MetAP
`
`(methionine aminopeptidase), an inhibitor of nuclear export of proteins CRM1, a DPPIV inhibitor,
`
`proteasome inhibitors,
`
`inhibitors of phosphory] transfer reactions in mitochondria, a protein synthesis
`
`inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a kinesin inhibitor, an HDAC
`
`inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA intercalator, a DNA minor groove
`
`binder and a DHFRinhibitor.
`
`[0021]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein the drug
`
`moiety is a maytansinoid.
`
`[0022]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein the
`
`maytansinoid 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).
`
`[0023]
`
`The antibody drug conjugate of any of the preceding embodiments in combination
`
`with another therapeutic agent.
`
`[0024]
`
`The antibody drug conjugate of any of the preceding embodiments in combination
`
`with a therapeutic agent listed in Table 18.
`
`[0025]
`
`The antibody drug conjugate of any of the preceding embodiments in combination
`
`with a BCL2 inhibitor, a BCL-XL inhibitor, a BCL2/BCL-XL inhibitor, an IAP inhibitor or a MEK
`
`inhibitor.
`
`[0026]
`
`The antibody drug conjugate of any of the preceding embodiments in combination
`
`with an immune modulatory molecule.
`
`[0027]
`
`An antibody drug conjugate of the formula:
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`~
`
`SOK
`
`o
`
`NB
`
`Ab
`
`11
`
`f—
`
`
`
`or a pharmaceutically acceptable salt thereof; wherein;
`
`Ab-sulfo-SPDB-DM4
`
`Abis an antibody or antigen binding fragmentthereof that specifically binds to haman CDH6,and n is
`
`an integer from | to 10.
`
`[0028]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein said
`
`antibody or antigen binding fragmentspecifically binds to an epitope of haman CDH6at (SEQ ID
`
`NO:4).
`
`[0029]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein said
`
`antibody or antigen binding fragmentthereof specifically binds human CDH6at (SEQ ID NO:534).
`
`[0030]
`
`The antibody drug conjugate of any of the preceding embodiments, wherein said Ab is
`
`an 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 HCDR1 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:210, (b) a LCDR2 of SEQ ID NO:211, (c) a LCDR3 of SEQ ID NO:212; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:213, (ec) 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
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`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO: 269, (e) a HCDR2 of SEQ
`
`ID NO:270, and (f) a HCDR3 of SEQ ID NO: 271;
`
`(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:310; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:311, (ce) a HCDR2 of SEQ
`
`ID NO:312, and (f) a HCDR3 of SEQ ID NO:313;
`
`(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 HCDR1 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 HCDR1 of SEQ ID NO:31, (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 HCDR1 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 HCDR1 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 HCDR1 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 region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:84, (b) a LCDR2 of SEQ ID NO:85, (c) a LCDR3 of SEQ ID NO:86; and a
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`heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:87, (e) a HCDR2 of SEQ ID
`
`NO: 88, and (f) a HCDR3 of SEQ ID NO: 89;
`
`(xi) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:98, (b) a LCDR2 of SEQ ID NO:99, (c) a LCDR3 of SEQ ID NO:100; and a
`
`heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:101, (ce) a HCDR2 of SEQ
`
`ID NO:102, and (f) a HCDR3 of SEQ ID NO: 103;
`
`(xii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:112, (b) a LCDR2 of SEQ ID NO:113, (c) a LCDR3 of SEQ ID NO:114; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:115, (ce) a HCDR2 of SEQ
`
`ID NO:116, and (f) a HCDR3 of SEQ ID NO:117;
`
`(xiii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:126, (b) a LCDR2 of SEQ ID NO:127, (c) a LCDR3 of SEQ ID NO:128; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:129, (ec) a HCDR2 of SEQ
`
`ID NO:130, and (f) a HCDR3 of SEQ ID NO:131;
`
`(xiv) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:140, (b) a LCDR2 of SEQ ID NO:141, (c) a LCDR3 of SEQ ID NO:142; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:143, (ec) a HCDR2 of SEQ
`
`ID NO:144, and (f) a HCDR3 of SEQ ID NO: 145;
`
`(xv) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:154, (b) a LCDR2 of SEQ ID NO:155, (c) a LCDR3 of SEQ ID NO:156; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:157, (ce) aHCDR2 of SEQ
`
`ID NO:158, and (f) a HCDR3 of SEQ ID NO:159;
`
`(xvi) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO: 168, (b) a LCDR2 of SEQ ID NO:169, (c) a LCDR3 of SEQ ID NO:170; and
`
`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:171, (e¢) aHCDR2 of SEQ
`
`ID NO:172, and (f) a HCDR3 of SEQ ID NO:173;
`
`(xvii) a light chain variable region that comprises (a) a LCDR1 (CDR-Complementarity Determining
`
`Region) of SEQ ID NO:182, (b) a LCDR2 of SEQ ID NO:183, (c) a LCDR3 of SEQ ID NO:184; and
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`a heavy chain variable region that comprises: (d) a HCDR1 of SEQ ID NO:185, (ec) a HCDR2 of SEQ
`
`ID NO: 186, and (f) a HCDR3 of SE