Inhibitors of angiopoietin-like 4 protein, combinations, and their use

Abstract

Modulators of angiopoietin-like 4 protein are provided along with methods for their use in the treatment of diseases and pathological conditions. Combinations of ANGPTL4 antagonists and other therapeutics, e.g., anti-cancer agents, and methods of their use in the treatment of mammals susceptible to or diagnosed with cancer, or with relapse tumor growth or relapse cancer cell growth are also provided.

1 . A method of blocking or reducing tumor growth or growth of a cancer cell, said method comprising: 
 a) administering to the tumor or the cancer cell an effective amount of an anti-cancer agent; and    b) administering to the tumor or the cancer cell an effective amount of an angiopoietin-like 4 protein (ANGPTL4) antagonist,    wherein the combined effective amounts block or reduce tumor growth or growth of the cancer cell.    
     
     
         2 . The method of  claim 1 , wherein the anti-cancer comprises an anti-angiogenesis agent.  
     
     
         3 . The method of  claim 2 , wherein the anti-angiogenesis agent is a VEGF antagonist.  
     
     
         4 . The method of  claim 3 , wherein the VEGF antagonist is an anti-VEGF antibody.  
     
     
         5 . The method of  claim 4 , wherein the anti-VEGF antibody is humanized A4.6.1.  
     
     
         6 . The method of  claim 1 , wherein the ANGPTL4 antagonist is an anti-ANGPTL4 antibody.  
     
     
         7 . The method of  claim 6 , wherein the anti-ANGPTL4 antibody binds to ANGPTL4 (184-406).  
     
     
         8 . The method of  claim 1 , wherein the ANGPTL4 antagonist is an anti-αVβ5 antibody.  
     
     
         9 . The method of  claim 4 ,  6  or  8 , wherein the antibody is a humanized antibody.  
     
     
         10 . The method of  claim 1 , wherein the ANGPTL4 antagonist comprises a SiRNA molecule.  
     
     
         11 . The method of  claim 10 , wherein the SiRNA molecule is an ANGPTL4-SiRNA molecule.  
     
     
         12 . The method of  claim 11 , wherein the ANGPTL4-SiRNA molecule targets a DNA sequence of a nucleic acid encoding ANGPTL4, wherein the DNA sequence comprises at least GTGGCCAAGCCTGCCCGAAGA.  
     
     
         13 . The method of  claim 1 , further comprising administering to the tumor or the cancer cell a third anti-cancer agent.  
     
     
         14 . The method of  claim 13 , wherein the third anti-cancer agent is a chemotherapeutic agent.  
     
     
         15 . The method of  claim 13 , wherein the third anti-cancer agent is another angiogenesis inhibitor.  
     
     
         16 . The method of  claim 1 , wherein the administration steps (a) and (b) are performed sequentially.  
     
     
         17 . The method of  claim 1 , wherein the administration steps (a) and (b) are performed concurrently.  
     
     
         18 . The method of  claim 1 , wherein the administration steps (a) and (b) are performed both sequentially and concurrently.  
     
     
         19 . The method of  claim 1 , wherein the administration steps is performed in any order.  
     
     
         20 . The method of  claim 1 , wherein the tumor or the cancer cell is in a subject.  
     
     
         21 . The method of  claim 20 , wherein the subject is a human.  
     
     
         22 . The method of  claim 20 , wherein the subject has relapse tumor growth or relapse cancer cell growth.  
     
     
         23 . A method of blocking or reducing tumor growth or growth of a cancer cell in a subject, said method comprising: 
 administering to the subject a combination composition comprising an effective amount of anti-angiogenesis agent and an effective amount of an angiopoietin-like 4 (ANGPTL4) antagonist, wherein the combined effective amounts block or reduce tumor growth or growth of the cancer cell.    
     
     
         24 . The method of  claim 23 , further comprising administering an additional agent, wherein the additional agent is an anti-cancer agent.  
     
     
         25 . A method of blocking or reducing relapse tumor growth or a relapse cancer cell growth in a subject, the method comprising: 
 administering to the subject an effective amount of an angiopoietin-like 4 (ANGPTL4) antagonist, wherein the subject was or is concurrently undergoing cancer therapy with an anti-cancer agent and wherein the administration of the effective amount of the ANGPTL4 antagonist blocks or reduces the relapse tumor growth or relapse cancer cell growth.    
     
     
         26 . The method of  claim 25 , wherein the anti-cancer agent is one or more chemotherapeutic agents.  
     
     
         27 . The method of  claim 25 , wherein the anti-cancer agent comprises an anti-angiogenesis agent.  
     
     
         28 . The method of  claim 27 , wherein the anti-angiogenesis agent comprises an anti-VEGF inhibitor.  
     
     
         29 . The method of  claim 28 , wherein the anti-VEGF inhibitor is an anti-VEGF antibody.  
     
     
         30 . The method of  claim 29 , wherein the anti-VEGF antibody is humanized A4.6.1.  
     
     
         31 . The method of  claim 25 , wherein the ANGPTL4 antagonist is an anti-ANGPTL4 antibody.  
     
     
         32 . The method of  claim 25 , wherein the ANGPTL4 antagonist is an anti-αVβ5 antibody.  
     
     
         33 . The method of  claim 29 ,  31 , or  32 , wherein the antibody is a humanized antibody.  
     
     
         34 . The method of  claim 25 , wherein the ANGPTL4 antagonist comprises a SiRNA molecule.  
     
     
         35 . The method of  claim 34 , wherein the SiRNA molecule is an ANGPTL4-SiRNA molecule.  
     
     
         36 . The method of  claim 35 , wherein the ANGPTL4-SiRNA molecule targets a DNA sequence of a nucleic acid encoding ANGPTL4, wherein the DNA sequence comprises at least GTGGCCAAGCCTGCCCGAAGA.  
     
     
         37 . The method of  claim 25 , further comprising administering an additional agent, wherein the additional agent is an anti-cancer agent.  
     
     
         38 . A method of blocking or reducing tumor growth or growth of a cancer cell, the method comprising administering to the tumor or cancer cell an effective amount of an angiopoietin-like 4 (ANGPTL4) antagonist, wherein the ANGPTL4 antagonist is an antibody that binds to ANGPTL4 (184-406) and wherein the effective amount blocks or reduces tumor growth or growth of the cancer cell.  
     
     
         39 . A composition comprising an antibody that binds to ANGPTL4 (184-406) and a VEGF antagonist.  
     
     
         40 . A composition comprising an ANGPTL4-SiRNA molecule, wherein the ANGPTL4-SiRNA molecule targets a DNA sequence of a nucleic acid encoding ANGPTL4, wherein the DNA sequence comprises at least GTGGCCAAGCCTGCCCGAAGA.  
     
     
         41 . A kit comprising a first amount of an anti-angiogenesis agent, a second amount of an angiopoietin-like 4 (ANGPTL4) agent and a pharmaceutically acceptable carrier, vehicle, or diluent, and a container.  
     
     
         42 . A kit comprising an amount of an anti-angiogenesis agent and a pharmaceutically acceptable carrier, vehicle, or diluent in a first unit dosage form; an amount of an angiopoietin-like 4 (ANGPTL4) antagonist and a pharmaceutically acceptable carrier, vehicle, or diluent in a second unit dosage form; and a container.