Tumor necrosis factor (tnf) superfamily receptor igm antibodies and uses thereof

Abstract

This disclosure provides dimeric, pentameric, and hexameric Tumor Necrosis Factor (TNF) superfamily receptor protein binding molecules and methods of using such binding molecules to direct apoptosis-mediated killing of TNF receptor-expressing cells.

What is claimed is: 
     
         1 . An antibody comprising five bivalent binding units, and a J chain or variant thereof,
 wherein each binding unit comprises two IgM heavy chains and two immunoglobulin light chains, wherein each IgM heavy chain comprises a heavy chain variable region (VH) situated amino-terminal to a human IgM constant region, wherein each immunoglobulin light chain comprises a light chain variable region (VL) situated amino-terminal to a human immunoglobulin light chain constant region, wherein the VH and VL form an antigen binding domain that specifically binds to death domain containing receptor-5 (DR5),   and wherein each VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of the VH and VL amino acid sequences contained within SEQ ID NO: 7 and SEQ ID NO: 8, respectively.   
     
     
         2 . The antibody of  claim 1 , wherein the antibody can cross-link at least three DR5 proteins expressed on the surface of a cancer cell, thereby inducing DR5-mediated apoptosis of the cell, and wherein the antibody can induce DR5-mediated apoptosis in a DR5-expressing cancer cell at a higher potency than an equivalent amount of tigatuzumab. 
     
     
         3 . The antibody of  claim 1 , wherein the VH and VL comprise amino acid sequences at least 90% identical to the VH and VL amino acid sequences contained within SEQ ID NO: 7 and SEQ ID NO: 8, respectively. 
     
     
         4 . The antibody of  claim 2 , wherein the VH and VL comprise amino acid sequences at least 90% identical to the VH and VL amino acid sequences contained within SEQ ID NO: 7 and SEQ ID NO: 8, respectively. 
     
     
         5 . The antibody of  claim 1 , wherein the VH and VL regions comprising the amino acid sequences the VH and VL amino acid sequences contained within SEQ ID NO: 7 and SEQ ID NO: 8, respectively. 
     
     
         6 . The antibody of  claim 2 , wherein the VH and VL regions comprising the amino acid sequences the VH and VL amino acid sequences contained within SEQ ID NO: 7 and SEQ ID NO: 8, respectively. 
     
     
         7 . A composition comprising the antibody of  claim 1 . 
     
     
         8 . A method of treating cancer comprising administering to a subject in need of treatment an effective amount of the antibody of  claim 1 , wherein the cancer cells in the subject express DR5, wherein the subject is human. 
     
     
         9 . The method of  claim 8 , wherein the antibody can induce greater apoptosis of cancer cells than of normal hepatocytes. 
     
     
         10 . A method of treating cancer comprising administering to a subject in need of treatment an effective amount of the antibody of  claim 5 , wherein the cancer cells in the subject express DR5, wherein the subject is human. 
     
     
         11 . The method of  claim 10 , wherein the antibody can induce greater apoptosis of cancer cells than of normal hepatocytes. 
     
     
         12 . A method of treating cancer comprising administering to a subject in need of treatment an effective amount of the antibody of  claim 6 , wherein the cancer cells in the subject express DR5, wherein the subject is human. 
     
     
         13 . The method of  claim 12 , wherein the antibody can induce greater apoptosis of cancer cells than of normal hepatocytes. 
     
     
         14 . An antibody comprising five bivalent binding units, and a J chain or variant thereof,
 wherein each binding unit comprises two IgM heavy chains and two immunoglobulin light chains, wherein each IgM heavy chain comprises a heavy chain variable region (VH) situated amino-terminal to a human IgM constant region, wherein each immunoglobulin light chain comprises a light chain variable region (VL) situated amino-terminal to a human immunoglobulin light chain constant region, wherein the VH and VL form an antigen binding domain that specifically binds to death domain containing receptor-5 (DR5),   wherein each VH and VL comprise six immunoglobulin complementarity determining regions HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the CDRs of the VH and VL amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 6, respectively.   
     
     
         15 . The antibody of  claim 14 , wherein the antibody can cross-link at least three DR5 proteins expressed on the surface of a cancer cell, thereby inducing DR5-mediated apoptosis of the cell, and wherein the antibody can induce DR5-mediated apoptosis in a DR5-expressing cancer cell at a higher potency than an equivalent amount of conatumumab. 
     
     
         16 . The antibody of  claim 14 , wherein the VH and VL comprise amino acid sequences at least 90% identical to SEQ ID NO: 5 and SEQ ID NO: 6, respectively. 
     
     
         17 . The antibody of  claim 15 , wherein the VH and VL comprise amino acid sequences at least 90% identical to SEQ ID NO: 5 and SEQ ID NO: 6, respectively. 
     
     
         18 . The antibody of  claim 14 , wherein the VH and VL comprise the VH and VL of conatumumab. 
     
     
         19 . The antibody of  claim 15 , wherein the VH and VL comprise the VH and VL of conatumumab. 
     
     
         20 . A composition comprising the antibody of  claim 14 . 
     
     
         21 . A method of treating cancer comprising administering to a subject in need of treatment an effective amount of the antibody of  claim 14 , wherein the cancer cells in the subject express DR5, wherein the subject is human. 
     
     
         22 . The method of  claim 21 , wherein the antibody can induce greater apoptosis of cancer cells than of normal hepatocytes. 
     
     
         23 . A method of treating cancer comprising administering to a subject in need of treatment an effective amount of the antibody of  claim 16 , wherein the cancer cells in the subject express DR5, wherein the subject is human. 
     
     
         24 . The method of  claim 23 , wherein the antibody can induce greater apoptosis of cancer cells than of normal hepatocytes. 
     
     
         25 . A method of treating cancer comprising administering to a subject in need of treatment an effective amount of the antibody of  claim 18 , wherein the cancer cells in the subject express DR5, wherein the subject is human. 
     
     
         26 . The method of  claim 25 , wherein the antibody can induce greater apoptosis of cancer cells than of normal hepatocytes.