NOVEL SEZ6 MODULATORS AND METHODS OF USE

1 .- 19 . (canceled)

20 . A method of treating (i) chemoresistant small cell lung cancer or (ii) medullary thyroid cancer, comprising administering to a subject in need thereof an antibody drug conjugate comprising a monoclonal antibody conjugated, linked, or otherwise associated with a cytotoxic agent, wherein the monoclonal antibody binds to a human SEZ6 protein.

21 . The method of claim 20 , wherein the monoclonal antibody is selected from the group consisting of a chimeric antibody, humanized antibody, and CDR-grafted antibody.

22 . The method of claim 20 , wherein the monoclonal antibody comprises three complementarity determining regions of a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 190, and three complementarity determining regions of a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 191.

23 . The method of claim 22 , wherein the monoclonal antibody comprises residues 23-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 26-32 of SEQ ID NO: 191 for CDR-H1, residues 50-58 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Chothia.

24 . The method of claim 22 , wherein the monoclonal antibody comprises residues 30-36 of SEQ ID NO: 190 for CDR-L1, residues 46-55 of SEQ ID NO: 190 for CDR-L2, residues 89-96 of SEQ ID NO: 190 for CDR-L3, residues 30-35 of SEQ ID NO: 191 for CDR-H1, residues 47-58 of SEQ ID NO: 191 for CDR-H2 and residues 93-101 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to MacCallum.

25 . The method of claim 22 , wherein the monoclonal antibody comprises residues 24-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 31-35 of SEQ ID NO: 191 for CDR-H1, residues 50-65 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Kabat.

26 . The method of claim 20 , wherein the monoclonal antibody is an internalizing antibody.

27 . The method of claim 20 , wherein the cytotoxic agent is a pyrrolobenzodiazepine, a duocarmycin, an amanitin, an auristatin, a maytansinoid, a calicheamicin, or a radioisotope.

28 . The method of claim 22 , wherein the cytotoxic agent is a calicheamicin.

29 . The method of claim 20 , wherein the antibody drug conjugate comprises the formula M-[L-D]n wherein:

a) M comprises the monoclonal antibody;

b) L comprises an optional linker;

c) D comprises a drug, which is the cytotoxic agent; and

d) n is an integer from 1 to 20.

30 . The method of claim 29 , wherein the monoclonal antibody is conjugated to the cytotoxic agent via a linker.

31 . The method of claim 30 , wherein the linker comprises a non-cleavable linker.

32 . The method of claim 20 for treating chemoresistant small cell lung cancer.

33 . The method of claim 32 , wherein the small cell lung cancer is resistant to a platinum based agent.

34 . The method of claim 33 , wherein the platinum based agent is cisplatin.

35 . The method of claim 20 for treating medullary thyroid cancer.

36 . A method of treating chemoresistant small cell lung cancer comprising administering to a subject in need thereof an antibody drug conjugate comprising a humanized antibody conjugated to a cytotoxic agent,

wherein the humanized antibody comprises three complementarity determining regions of a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 190, and three complementarity determining regions of a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 191, and

wherein the cytotoxic agent comprises a calicheamicin.

37 . The method of claim 36 , wherein the monoclonal antibody comprises:

(a) residues 23-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 26-32 of SEQ ID NO: 191 for CDR-H1, residues 50-58 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Chothia;

(b) residues 30-36 of SEQ ID NO: 190 for CDR-L1, residues 46-55 of SEQ ID NO: 190 for CDR-L2, residues 89-96 of SEQ ID NO: 190 for CDR-L3, residues 30-35 of SEQ ID NO: 191for CDR-H1, residues 47-58 of SEQ ID NO: 191 for CDR-H2 and residues 93-101 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to MacCallum; or

(c) residues 24-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 31-35 of SEQ ID NO: 191 for CDR-H1, residues 50-65 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Kabat.

38 . The method of claim 37 , wherein the small cell lung cancer is resistant to a platinum based agent.

39 . The method of claim 38 , wherein the platinum based agent is cisplatin.

40 . A method of treating medullary thyroid cancer comprising administering to a subject in need thereof an antibody drug conjugate comprising a humanized antibody conjugated to a cytotoxic agent,

wherein the humanized antibody comprises three complementarity determining regions of a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 190, and three complementarity determining regions of a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 191, and

wherein the cytotoxic agent comprises a calicheamicin.

41 . The method of claim 40 , wherein the monoclonal antibody comprises:

(a) residues 23-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 26-32 of SEQ ID NO: 191 for CDR-H1, residues 50-58 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Chothia;

(b) residues 30-36 of SEQ ID NO: 190 for CDR-L1, residues 46-55 of SEQ ID NO: 190 for CDR-L2, residues 89-96 of SEQ ID NO: 190 for CDR-L3, residues 30-35 of SEQ ID NO: 191 for CDR-H1, residues 47-58 of SEQ ID NO: 191 for CDR-H2 and residues 93-101 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to MacCallum; or

(c) residues 24-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 31-35 of SEQ ID NO: 191 for CDR-H1, residues 50-65 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Kabat.