SP35 Antibodies And Uses Thereof

Abstract

Endogenous Sp35 is a negative regulator for neuronal survival, axon regeneration, oligodendrocyte differentiation and myelination. Molecules that block endogenous Sp35 function, such anti-Sp35 antibodies can be used as therapeutics for the treatment of neuron and oligodendrocyte dysfunction. The present invention provides antibodies specific for Sp35, and methods of using such antibodies as antagonists of endogenous Sp35 function. The invention further provides specific hybridoma and phage library-derived monoclonal antibodies, nucleic acids encoding these antibodies, and vectors and host cells comprising these antibodies. The invention further provides methods of promoting oligodendrocyte survival and myelination in a vertebrate, comprising administering to a vertebrate in need of such treatment an effective amount of an anti-Sp35 antibody.

1 - 30 . (canceled) 
     
     
         31 . One or more nucleic acid molecules encoding an immunoglobulin heavy chain variable region (VH) and an immunoglobulin light chain variable region (VL), wherein the VH and VL comprise CDR1, CDR2, and CDR3 regions,
 wherein the CDR1, CDR2, and CDR3 regions of the VH comprise the amino acid sequences of SEQ ID NO:436, SEQ ID NO:437 and SEQ ID NO:438, respectively, and   the CDR1, CDR2, and CDR3 regions of the VL comprise the amino acid sequences of SEQ ID NO:442, SEQ ID NO:443 and SEQ ID NO:444, respectively, and   wherein an antibody comprising said VH and VL, or an antigen-binding fragment thereof, can specifically bind to Sp35.   
     
     
         32 . The one or more nucleic acid molecules of  claim 31 , wherein the VH comprises the amino acid sequence of the VH region of SEQ ID NO:435. 
     
     
         33 . The one or more nucleic acid molecules of  claim 31 , wherein the VL comprises the amino acid sequence of the VL region of SEQ ID NO:434. 
     
     
         34 . The one or more nucleic acid molecules of  claim 31 , wherein the VH comprises the amino acid sequence of the VH region of SEQ ID NO:435 and the VL comprises the amino acid sequence of the VL region of SEQ ID NO:434. 
     
     
         35 . The one or more nucleic acid molecules of  claim 31 , wherein the nucleic acid molecule further comprises a nucleic acid sequence encoding an aglycosylated heavy chain constant region. 
     
     
         36 . The one or more nucleic acid molecules of  claim 32 , wherein the nucleic acid molecule further comprises a nucleic acid sequence encoding an aglycosylated heavy chain constant region. 
     
     
         37 . The one or more nucleic acid molecules of  claim 33 , wherein the nucleic acid molecule further comprises a nucleic acid sequence encoding an aglycosylated heavy chain constant region. 
     
     
         38 . The one or more nucleic acid molecules of  claim 34 , wherein the nucleic acid molecule further comprises a nucleic acid sequence encoding an aglycosylated heavy chain constant region. 
     
     
         39 . The one or more nucleic acid molecules of  claim 31 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:435. 
     
     
         40 . The one or more nucleic acid molecules of  claim 31 , wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:434. 
     
     
         41 . The one or more nucleic acid molecules of  claim 31 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:435 and a light chain comprising the amino acid sequence of SEQ ID NO:434 
     
     
         42 . A vector or vectors comprising the one or more nucleic acids of  claim 31 . 
     
     
         43 . A vector or vectors comprising the one or more nucleic acids of  claim 34 . 
     
     
         44 . A vector or vectors comprising the one or more nucleic acids of  claim 41 . 
     
     
         45 . A polypeptide comprising an immunoglobulin heavy chain variable region (VH) comprising CDR1, CDR2, and CDR3 regions, wherein the CDR1, CDR2, and CDR3 regions of the VH comprise the amino acid sequences of SEQ ID NO:436, SEQ ID NO:437, and SEQ ID NO:438, and wherein an antibody comprising said VH or an antigen-binding fragment thereof can specifically bind to Sp35. 
     
     
         46 . The polypeptide of  claim 45 , wherein the polypeptide further comprises an aglycosylated heavy chain constant region. 
     
     
         47 . The polypeptide of  claim 45 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:435. 
     
     
         48 . A method for treating multiple sclerosis comprising administering to an animal in need of said treatment an effective amount of the polypeptide of  claim 45 . 
     
     
         49 . A method for treating multiple sclerosis comprising administering to an animal in need of said treatment an effective amount of the polypeptide of  claim 46 . 
     
     
         50 . An antibody produced by
 (a) culturing a host cell comprising a first nucleic acid molecule comprising a   nucleic acid sequence encoding a VH region comprising CDR1, CDR2, and CDR3 regions and a second nucleic acid molecule comprising a nucleic acid sequence encoding a VL region comprising CDR1, CDR2, and CDR3 regions, wherein the CDR1, CDR2, and CDR3 regions of said VH region comprise the amino acid sequences of SEQ ID NO:436, SEQ ID NO:437, and SEQ ID NO:438, and the CDR1, CDR2, and CDR3 regions of said VL region comprise the amino acid sequences of SEQ ID NO:442, SEQ ID NO:443, and SEQ ID NO:444, and wherein said VH and VL encoding nucleic acid sequences together encode an antibody which can specifically bind Sp35 or an antigen-binding fragment thereof and   (b) recovering said antibody or antigen-binding fragment thereof from the culture.