Novel sez6 modulators and methods of use

Abstract

Novel modulators, including antibodies and derivatives thereof, and methods of using such modulators to treat proliferative disorders are provided.

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.