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 . An antibody or antigen-binding fragment thereof that specifically binds LINGO-1, wherein the antibody or antigen-binding fragment thereof comprises
 a heavy chain variable region (VH) comprising complementarity determining regions (CDRs), CDRH1, CDRH2, and CDRH3 consisting of the amino acid sequences set forth in SEQ ID NO:410, SEQ ID NO:411, and SEQ ID NO:412, respectively; and   a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 consisting of the amino acid sequences set forth in SEQ ID NO:413, SEQ ID NO:414, and SEQ ID NO:415, respectively.   
     
     
         32 . The antibody or antigen-binding fragment thereof of  claim 31 , wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:416. 
     
     
         33 . The antibody or antigen-binding fragment thereof of  claim 31 , wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:417. 
     
     
         34 . The antibody or antigen-binding fragment thereof of  claim 31 , wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:419. 
     
     
         35 . The antibody or antigen-binding fragment thereof of  claim 31 , wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:416 and the VL comprises the amino acid sequence set forth in SEQ ID NO:417. 
     
     
         36 . The antibody or antigen-binding fragment thereof of  claim 31 , wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:416 and the VL comprises the amino acid sequence set forth in SEQ ID NO:419. 
     
     
         37 . 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 CDRH1, CDRH2, and CDRH3 regions of the VH comprise the amino acid sequences of SEQ ID NO:410, SEQ ID NO:411, and SEQ ID NO:412, respectively, and   the CDRL1, CDRL2, and CDRL3 regions of the VL comprise the amino acid sequences of SEQ ID NO:413, SEQ ID NO:414, and SEQ ID NO:415, respectively, and   wherein an antibody comprising said VH and VL, or an antigen-binding fragment thereof, can specifically bind to LINGO-1.   
     
     
         38 . The one or more nucleic acid molecules of  claim 37 , wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:416. 
     
     
         39 . The one or more nucleic acid molecules of  claim 37 , wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:417. 
     
     
         40 . The one or more nucleic acid molecules of  claim 37 , wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:419. 
     
     
         41 . The one or more nucleic acid molecules of  claim 37 , wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:416 and the VL comprises the amino acid sequence set forth in SEQ ID NO:417. 
     
     
         42 . The one or more nucleic acid molecules of  claim 37 , wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:416 and the VL comprises the amino acid sequence set forth in SEQ ID NO:419. 
     
     
         43 . A vector or vectors comprising the one or more nucleic acid molecules of  claim 37 . 
     
     
         44 . A host cell comprising the vector or vectors of  claim 43 . 
     
     
         45 . A method of producing an antibody or antigen-binding fragment thereof that specifically binds LINGO-1, the method comprising culturing the host cell of  claim 44  in a cell culture medium and isolating the antibody or antigen-binding fragment thereof from the cell culture medium. 
     
     
         46 . A method for treating multiple sclerosis comprising administering to a human subject in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 31 . 
     
     
         47 . A method for treating multiple sclerosis comprising administering to a human subject in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 35 . 
     
     
         48 . A method for treating multiple sclerosis comprising administering to a human subject in need of said treatment an effective amount of the antibody or antigen-binding fragment thereof of  claim 36 . 
     
     
         49 . An antibody or antigen-binding fragment thereof that specifically binds LINGO-1, wherein the antibody or antigen-binding fragment thereof comprises
 a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO:432; and   a light chain variable region (VL) comprising the amino acid sequences set forth in SEQ ID NO:431.