Lymphotoxin-beta, lymphotoxin-beta Complexes, pharmaceutical preparations and therapeutic uses thereof

Abstract

This invention relates to lymphotoxin-β, a lymphocyte membrane type protein. This protein is found on the surface of a number of cells, including phorbol ester (PMA) stimulated T cell hybridoma II-23.D7 cells. This invention also relates to complexes formed between lymphotoxin-β and other peptides such as lymphotoxin-α and to complexes comprising multiple subunits of lymphotoxin-β. These proteins and complexes are useful in holding LT-α formed within the cell on the cell surface where the LT-α/LT-β complex may act as an inflammation regulating agent, a tumor growth inhibiting agent, a T cell inhibiting agent, a T cell activating agent, an autoimmune disease regulating agent, or an HIV inhibiting agent. Furthermore, the antitumor activity of the LT-α/LT-β complex may be delivered to tumor cells by tumor infiltrating lymphocytes (TILs) transfected with the gene for LT-β.

1 - 28 . (canceled)  
     
     
         29 . A composition comprising an antibody, or fragment thereof, that specifically binds a lymphotoxin-β polypeptide, and a pharmaceutically-acceptable carrier.  
     
     
         30 . The composition of  claim 29 , wherein the antibody specifically binds a soluble lymphotoxin-β polypeptide.  
     
     
         31 . The composition of  claim 29 , wherein the antibody specifically binds a polypeptide complex comprising a first polypeptide which is lymphotoxin-β or a fragment thereof and a second polypeptide selected from the group consisting of lymphotoxin-α, native human or animal lymphotoxin, recombinant lymphotoxin, soluble lymphotoxin, secreted lymphotoxin, or lymphotoxin or lymphotoxin-active fragments of any of the above.  
     
     
         32 . The composition of  claim 31 , wherein the second polypeptide is lymphotoxin-α.  
     
     
         33 . The composition of  claim 29 , wherein the antibody specifically binds surface lymphotoxin.  
     
     
         34 . The composition of  claim 29 , wherein the antibody specifically binds a polypeptide selected from the group consisting of: 
 (a) an amino acid sequence defined by SEQ ID NO:2;    (b) an amino acid sequence defined by SEQ ID NO:4;    (c) an amino acid sequence defined by SEQ ID NO:6; and    (d) an amino acid sequence represented by the following formula:      X-SEQ ID NO:6,    wherein X comprises one or more of the amino acid residues starting from the carboxyl terminus reading toward the amino terminus of SEQ ID NO:8.    
     
     
         35 . The composition of  claim 29 , wherein the antibody specifically binds a polypeptide comprising an amino acid sequence that is encoded by a DNA molecule selected from the group consisting of: 
 (a) a DNA sequence defined by SEQ ID NO:1;    (b) a DNA sequence defined by SEQ ID NO:3;    (c) a DNA sequence defined by SEQ ID NO:5; and    (d) a DNA sequence represented by the following formula:      X-SEQ ID NO:5,    wherein X comprises one or more of the nucleoside triplets starting from the 3′ end reading toward the 5′ of SEQ ID NO:7.    
     
     
         36 . The composition of  claim 29 , wherein the antibody specifically binds a polypeptide complex comprising a first polypeptide selected from the group consisting of an amino acid sequence selected from the group consisting of: 
 (a) an amino acid sequence defined by SEQ ID NO:2;    (b) an amino acid sequence defined by SEQ ID NO:4;    (c) an amino acid sequence defined by SEQ ID NO:6; and    (d) a soluble lymphotoxin-beta peptide represented by the following formula:      X-SEQ ID NO:6,    wherein X comprises one or more of the amino acid residues starting from the carboxyl terminus reading to the amino terminus of SEQ ID NO:8; and a second polypeptide selected from the group consisting of lymphotoxin-alpha, native human or animal lymphotoxin, recombinant lymphotoxin, soluble lymphotoxin, secreted lymphotoxin, or lymphotoxin or lymphotoxin-active fragments of any of the above.    
     
     
         37 . The composition of any of claims  29 - 36 , wherein the antibody is a monoclonal antibody.  
     
     
         38 . The composition of any of claims  29 - 36 , wherein the antibody is a neutralizing antibody.  
     
     
         39 . The composition of  claim 37 , wherein the monoclonal antibody is a neutralizing antibody.  
     
     
         40 . The composition of any of claims  29 - 36 , wherein the composition is formulated for parenteral administration.  
     
     
         41 . The composition of  claim 40 , wherein the parenteral administration is selected from the group consisting of subcutaneous and intravenous administration.