Anti-lymphotoxin-beta receptor antibodies as anti-tumor agents

Abstract

This invention relates to compositions and methods useful for activating LT-β receptor signaling, which in turn elicits potent anti-proliferative effects on tumor cells. More particularly, this invention relates to lymphotoxin heteromeric complexes formed between lymphotoxin-a and multiple subunits of lymphotoxin-β, which induce cytotoxic effects on tumor cells in the presence of lymphotoxin-β receptor activating agents. Also within the scope of this invention are antibodies directed against the lymphotoxin-β receptor which act as lymphotoxin-β receptor activating agents alone or in combination with other lymphotoxin-β receptor activating agents either in the presence or absence of lymphotoxin-a/β complexes. A screening method for selecting such antibodies is provided. This invention also relates to compositions and methods using cross-linked anti-lymphotoxin-β receptor antibodies either alone or in the presence of other lymphotoxin-β receptor activating agents to potentiate tumor cell cytotoxicity.

1 - 32 . (canceled) 
   
   
       33 . A method for treating or reducing the advancement, severity or effects of neoplasia comprising the step of administering a therapeutically effective amount of at least one LT-β-R activating agent and a pharmaceutically acceptable carrier. 
   
   
       34 . The method according to  claim 33 , wherein at least one LT-β-R activating agent comprises an anti-LT-β-R antibody. 
   
   
       35 . The method according to  claim 34 , wherein the anti-LT-β-R antibody is CBE11. 
   
   
       36 . A method for selecting a LT-β-R activating agent which acts in the presence of LT-α/β heteromeric complexes comprising the steps of:
 a) culturing tumor cells in the presence of LT-α/β heteromeric complexes, an effective amount of a first LT-β-R activating agent and a second putative LT-β-R activating agent; and   b) determining whether the second putative LT-β-R activating agent increases the anti-tumor activity of the LT-α/β heteromeric complex in the presence of the first LT-β-R activating agent.   
   
   
       37 . The method according to  claim 36 , wherein the first LT-β-R activating agent is IFN-γ. 
   
   
       38 . The method according to  claim 36 , wherein the LT-α/β heteromeric complex has a LT-α1/β2 stoichiometry. 
   
   
       39 . A pharmaceutical composition comprising a therapeutically effective amount of a LT-α/β heteromeric complex and a pharmaceutically acceptable carrier. 
   
   
       40 . The pharmaceutical composition according to  claim 39 , wherein the LT-α/β heteromeric complex has a LT-α1/β2 stoichiometry. 
   
   
       41 . The pharmaceutical composition according to  claim 39 , wherein the LT-α/β heteromeric complex is soluble. 
   
   
       42 . The pharmaceutical composition according to  claim 39 , further comprising a therapeutically effective amount of at least one LT-β-R activating agent. 
   
   
       43 . The pharmaceutical composition according to  claim 42 , wherein one LT-β-R activating agent is IFN-γ. 
   
   
       44 . The pharmaceutical composition according to  claim 42 , wherein one LT-β-R activating agent is an anti-LT-β-R antibody. 
   
   
       45 . The pharmaceutical composition according to  claim 44 , wherein the anti-LT-β-R antibody is a monoclonal antibody. 
   
   
       46 . The pharmaceutical composition according to  claim 45 , wherein the anti-LT-β-R monoclonal antibody is selected from the group consisting of anti-LT-fi-R mAb BKA11, CDH10, BCG6, and BHA10. 
   
   
       47 - 70 . (canceled) 
   
   
       71 . An isolated anti-LT-β-R antibody comprising a light chain comprising antigen binding regions from a BHA10 mouse monoclonal antibody (ATCC Accession No. HB11795), and a heavy chain comprising antigen binding regions from the BHA10 mouse monoclonal antibody (ATCC Accession No. HB11795). 
   
   
       72 . The anti-LT-β-R antibody of  claim 71 , wherein the antibody is chimeric or multivalent. 
   
   
       73 . The anti-LT-β-R antibody of  claim 71 , wherein the antibody is humanized. 
   
   
       74 . The anti-LT-β-R antibody of  claim 73 , wherein the antibody comprises a human IgG constant region. 
   
   
       75 . The anti-LT-β-R antibody of  claim 74 , wherein the IgG constant region is an IgG1 constant region. 
   
   
       76 . The anti-LT-β-R antibody of  claim 74 , wherein the antibody is a F(ab) 2  fragment.