Use of DR6 and p75 Antagonists to Promote Survival of Cells of the Nervous System

Abstract

The present invention relates to Death Receptor-6 (DR6) proteins which are members of the tumor necrosis factor (TNF) receptor family, and have now been shown to be important for regulating apoptosis in cells of the nervous system. In addition, it has been discovered that p75 is a ligand for DR6. As a result, this invention relates to methods for inhibiting the interaction of DR6 and p75 using DR6 and/or p75 antagonists. In addition, the methods described herein include methods of promoting survival of cells of the nervous system using DR6 antagonists, optionally in combination with p75 antagonists, and methods of treating neurodegenerative conditions by the administration of a DR6 antagonists, optionally in combination with a p75 antagonist.

1 - 76 . (canceled) 
     
     
         77 . A method of treating a condition associated with oligodendrocyte death or lack of differentiation comprising administering a therapeutically effective amount of a DR6 antagonist wherein the DR6 antagonist is a soluble DR polypeptide, a DR6 antagonist polynucleotide, or an aptamer. 
     
     
         78 - 130 . (canceled) 
     
     
         131 . A method of inhibiting the binding of DR6 to p75 comprising contacting a p75 polypeptide or a DR6 polypeptide with a p75 antagonist under conditions wherein binding of DR6 to p75 is inhibited. 
     
     
         132 . (canceled) 
     
     
         133 . A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that can specifically bind to DR6 and that inhibits the binding of DR6 to p75 and a pharmaceutically acceptable carrier. 
     
     
         134 . The pharmaceutical composition of  claim 133 , wherein the composition is formulated for parenteral administration. 
     
     
         135 . The pharmaceutical composition of  claim 133 , wherein the composition comprises an effective amount of surfactant. 
     
     
         136 . The pharmaceutical composition of  claim 133 , wherein the composition comprises an effective amount of preservative. 
     
     
         137 . The pharmaceutical composition of  claim 133 , wherein the antibody or fragment binds to an epitope in amino acids 133-189 of SEQ ID NO:2. 
     
     
         138 . The pharmaceutical composition of  claim 134 , wherein the antibody or fragment binds to an epitope in amino acids 133-189 of SEQ ID NO:2. 
     
     
         139 . The pharmaceutical composition of  claim 135 , wherein the antibody or fragment binds to an epitope in amino acids 133-189 of SEQ ID NO:2. 
     
     
         140 . The pharmaceutical composition of  claim 136 , wherein the antibody or fragment binds to an epitope in amino acids 133-189 of SEQ ID NO:2. 
     
     
         141 . The pharmaceutical composition of  claim 133 , wherein the antibody or fragment can specifically bind to the same DR6 epitope as an antibody comprising a heavy chain variable region (VH) comprising the amino acids of SEQ ID NO: 127 and a light chain variable region (VL) comprising the amino acids of SEQ ID NO: 132. 
     
     
         142 . The pharmaceutical composition of  claim 134 , wherein the antibody or fragment can specifically bind to the same DR6 epitope as an antibody comprising a heavy chain variable region (VH) comprising the amino acids of SEQ ID NO: 127 and a light chain variable region (VL) comprising the amino acids of SEQ ID NO: 132. 
     
     
         143 . The pharmaceutical composition of  claim 135 , wherein the antibody or fragment can specifically bind to the same DR6 epitope as an antibody comprising a heavy chain variable region (VH) comprising the amino acids of SEQ ID NO: 127 and a light chain variable region (VL) comprising the amino acids of SEQ ID NO: 132. 
     
     
         144 . The pharmaceutical composition of  claim 136 , wherein the antibody or fragment can specifically bind to the same DR6 epitope as an antibody comprising a heavy chain variable region (VH) comprising the amino acids of SEQ ID NO: 127 and a light chain variable region (VL) comprising the amino acids of SEQ ID NO: 132. 
     
     
         145 . An isolated antibody or antigen-binding fragment thereof that can specifically bind to the same DR6 epitope as an antibody comprising a heavy chain variable region (VH) comprising the amino acids of SEQ ID NO: 127 and a light chain variable region (VL) comprising the amino acids of SEQ ID NO: 132, wherein the antibody or fragment is chimeric or humanized. 
     
     
         146 . A pharmaceutical composition comprising the antibody or fragment of  claim 145 . 
     
     
         147 . The pharmaceutical composition of  claim 145 , wherein the composition is formulated for parenteral administration. 
     
     
         148 . The pharmaceutical composition of  claim 145 , wherein the composition comprises an effective amount of surfactant. 
     
     
         149 . The pharmaceutical composition of  claim 145 , wherein the composition comprises an effective amount of preservative.