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 . A polypeptide comprising an immunoglobulin heavy chain variable region (VH) comprising CDR1, CDR2, and CDR3 regions, wherein the CDR1, CDR2, and CDR3 regions of said 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. 
     
     
         32 . The polypeptide of  claim 31 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:433. 
     
     
         33 . The polypeptide of  claim 31 , wherein the polypeptide further comprises an aglycosylated heavy chain constant region. 
     
     
         34 . The polypeptide of  claim 32 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:435. 
     
     
         35 . An antibody or antigen-binding fragment thereof comprising an immunoglobulin heavy chain variable region (VH) comprising CDR1, CDR2, and CDR3 regions and an immunoglobulin light chain variable region (VL) comprising CDR1, CDR2, and CDR3 regions,
 wherein the CDR1, CDR2, and CDR3 regions of said VH comprise the amino acid sequences of SEQ ID NO:436, SEQ ID NO:437, and SEQ ID NO:438   wherein the CDR1, CDR2, and CDR3 regions of said VL comprise the amino acid sequences of SEQ ID NO:442, SEQ ID NO:443, and SEQ ID NO:444,   wherein the antibody or antigen-binding fragment thereof can specifically bind to Sp35, and   wherein the antibody or antigen-binding fragment thereof is aglycosylated.   
     
     
         36 . The antibody or antigen-binding fragment of  claim 35 , which comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO:435. 
     
     
         37 . The antibody or antigen-binding fragment of  claim 36 , which comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO:434. 
     
     
         38 . A method for treating a disease or disorder associated with inhibition of neuronal growth in the central nervous system (CNS) comprising administering to an animal in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 35 . 
     
     
         39 . A method for treating a disease or disorder associated with inhibition of neuronal growth in the CNS comprising administering to an animal in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 37 . 
     
     
         40 . A method for treating a disease or disorder associated with inhibition of oligodendrocyte growth or differentiation comprising administering to an animal in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 35 . 
     
     
         41 . A method for treating a disease or disorder associated with inhibition of oligodendrocyte growth or differentiation comprising administering to an animal in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 37 . 
     
     
         42 . A method for treating a disease or disorder associated with demyelination or dysmyelination of a CNS neuron comprising administering to an animal in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 35 . 
     
     
         43 . A method for treating a disease or disorder associated with demyelination or dysmyelination of a CNS neuron comprising administering to an animal in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 37 . 
     
     
         44 . A method for treating multiple sclerosis comprising administering to an animal in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 35 . 
     
     
         45 . A method for treating multiple sclerosis comprising administering to an animal in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 37 . 
     
     
         46 . A method of inhibiting signal transduction by NgR1, comprising contacting the NgR1 with an effective amount of the antibody or antigen-binding fragment thereof of  claim 35 . 
     
     
         47 . A method of inhibiting signal transduction by NgR1, comprising contacting the NgR1 with an effective amount of the antibody or antigen-binding fragment thereof of  claim 37 . 
     
     
         48 . A method of decreasing inhibition of axonal growth of a CNS neuron, comprising contacting the neuron with an effective amount of the antibody or antigen-binding fragment thereof of  claim 35 . 
     
     
         49 . A method of decreasing inhibition of axonal growth of a CNS neuron, comprising contacting the neuron with an effective amount of the antibody or antigen-binding fragment thereof of  claim 37 . 
     
     
         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.