Dll3 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 . An isolated DLL3 modulator. 
     
     
         2 . The isolated DLL3 modulator of  claim 1 , wherein the DLL3 modulator comprises an antibody or immunoreactive fragment thereof. 
     
     
         3 . The isolated DLL3 modulator of  claim 2  wherein the antibody or immunoreactive fragment thereof comprises a monoclonal antibody. 
     
     
         4 . The isolated DLL3 modulator of  claim 3  wherein the monoclonal antibody is selected from the group consisting of chimeric antibodies, humanized antibodies and human antibodies. 
     
     
         5 . The isolated DLL3 modulator of  claims 3  or  4  wherein said monoclonal antibody or immunoreactive fragment thereof binds to a DLL3 protein N-terminal domain or DSL domain. 
     
     
         6 . The isolated DLL3 antibody modulator of any of  claims 2  to  5  wherein said antibody or immunoreactive fragment thereof comprises a light chain variable region having three complementarity determining regions and a heavy chain variable region having three complementarity determining regions wherein the heavy and light chain complementarity determining regions comprise at least one complementarity determining region set forth in  FIG. 11A  or  FIG. 11B . 
     
     
         7 . The isolated DLL3 antibody modulator of any of  claims 2  to  5  that competes for binding to a DLL3 protein with a reference antibody selected from the group consisting of SC16.3, SC16.4, SC16.5, SC16.7, SC16.8, SC16.10, SC16.11, SC16.13, SC16.15, SC16.18, SC16.19, SC16.20, SC16.21, SC16.22, SC16.23, SC16.25, SC16.26, SC16.29, SC16.30, SC16.31, SC16.34, SC16.35, SC16.36, SC16.38, SC16.39, SC16.41, SC16.42, SC16.45, SC16.47, SC16.49, SC16.50, SC16.52, SC16.55, SC16.56, SC16.57, SC16.58, SC16.61, SC16.62, SC16.63, SC16.65, SC16.67, SC16.68, SC16.72, SC16.73, SC16.78, SC16.79, SC16.80, SC16.81, SC16.84, SC16.88, SC16.101, SC16.103, SC16.104, SC16.105, SC16.106, SC16.107, SC16.108, SC16.109, SC16.110, SC16.111, SC16.113, SC16.114, SC16.115, SC16.116, SC16.117, SC16.118, SC16.120, SC16.121, SC16.122, SC16.123, SC16.124, SC16.125, SC16.126, SC16.129, SC16.130, SC16.131, SC16.132, SC16.133, SC16.134, SC16.135, SC16.136, SC16.137, SC16.138, SC16.139, SC16.140, SC16.141, SC16.142, SC16.143, SC16.144, SC16.147, SC16.148, SC16.149 and SC16.150 wherein binding of the DLL3 antibody modulator to the DLL3 protein is inhibited by at least 30%. 
     
     
         8 . The isolated DLL3 modulator of any of  claims 2  to  7  wherein said antibody comprises an internalizing antibody. 
     
     
         9 . The isolated DLL3 modulator of any of  claims 2  to  8  wherein said antibody further comprises a cytotoxic agent. 
     
     
         10 . A nucleic acid encoding an amino acid heavy chain variable region or an amino acid light chain variable region of an antibody or immunoreactive fragment thereof of  claims 1 - 8 . 
     
     
         11 . A host cell comprising the nucleic acid of  claim 10 . 
     
     
         12 . An antibody drug conjugate of the formula:
 M-[L-D]n or a pharmaceutically acceptable salt thereof wherein   a) M comprises a DLL3 modulator;   b) L comprises an optional linker;   c) D is a anti-proliferative agent; and   d) n is an integer from about 1 to about 20.   
     
     
         13 . The antibody drug conjugate of  claim 12  wherein said DLL3 modulator comprises an antibody or immunoreactive fragment thereof and said antibody or immunoreactive fragment thereof comprises a light chain variable region having three complementarity determining regions and a heavy chain variable region having three complementarity determining regions wherein the heavy and light chain complementarity determining regions comprise at least one complementarity determining region set forth in  FIG. 11A  or  FIG. 11B . 
     
     
         14 . The antibody drug conjugate of  claims 12  or  13  wherein said DLL3 modulator comprises an internalizing antibody. 
     
     
         15 . The isolated DLL3 modulator of any of  claims 1 - 9  or the antibody drug conjugate of  claims 12  or  14  for use in a medicine. 
     
     
         16 . The isolated DLL3 modulator of any of  claims 1 - 9  or the antibody drug conjugate of  claims 12  or  14  for the treatment of cancer in a patient wherein the cancer is selected from the group consisting of adrenal cancer, bladder cancer, cervical cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, prostate cancer and breast cancer. 
     
     
         17 . Use of a DLL3 modulator for the manufacture of a medicament for treating small cell lung cancer in a subject in need thereof. 
     
     
         18 . The medicament of  claim 17  wherein said DLL3 modulator comprises a monoclonal antibody. 
     
     
         19 . The medicament of any of  claims 17  or  18  wherein said DLL3 modulator binds to a DLL3 protein N-terminal domain or DSL domain. 
     
     
         20 . The medicament of any of  claims 17  to  19  wherein said DLL3 modulator comprises a cytotoxic agent.