Sp35 Antibodies and Uses Thereof

Abstract

Endogenous Sp35 is a negative regulator for neuronal survival, axon regeneration, oligodendrocyte differentiation and myelination (Negative Regulator). 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 - 212 . (canceled) 
     
     
         213 . A binding molecule which is capable of binding to the protein according to amino acids 34 to 551 of SEQ ID NO:2, with a dissociation constant <1000 nM. 
     
     
         214 . The binding molecule according to  claim 213  which binds to one or more of the sequences chosen from the group consisting of amino acids 66-426, 138-161, 210-233, 234-257, 258-281, 417-424, or 412-493 of SEQ ID NO:2. 
     
     
         215 . The binding molecule according to  claim 213 , which is capable of disinhibiting spinal cord myelin at a concentration of less than 3 μg/ml. 
     
     
         216 . The binding molecule according to  claim 213 , which is capable of increasing mean neurite length. 
     
     
         217 . The binding molecule according to  claim 213 , which comprises at least one antigen binding site chosen from the group consisting of:
 a sequence which selected from the group consisting of SEQ ID NO:380 or SEQ ID NO:161, and;   a sequence which is selected from the group consisting of SEQ ID NO:381 or SEQ ID NO:276.   
     
     
         218 . The binding molecule according to  claim 213 , which is an antibody or a fragment thereof. 
     
     
         219 . The binding molecule according to  claim 218  in which the constant part or fragment thereof of the human heavy chain is of the γ4 type and the constant part or fragment thereof of the human light chain is of the κ type. 
     
     
         220 . The binding molecule according to  claim 218 , which is a human or chimeric or humanized monoclonal antibody. 
     
     
         221 . A polynucleotide encoding a binding molecule according to  claim 218 . 
     
     
         222 . An expression vector comprising one or more polynucleotides according to  claim 221 . 
     
     
         223 . An expression system comprising a polynucleotide according to  claim 221 , when said expression system or part thereof is present in a compatible host cell. 
     
     
         224 . An isolated host cell which comprises an expression system according to  claim 223 . 
     
     
         225 . A pharmaceutical composition comprising a binding molecule according to  claim 213  together with at least one pharmaceutically acceptable carrier or diluent. 
     
     
         226 . A method treatment of diseases associated with the promotion of axonal regeneration comprising administering to a subject in need of such treatment an effective amount of a binding molecule according to  claim 213 . 
     
     
         227 . A binding molecule which is capable of binding to the protein according to amino acids 34 to 551 of SEQ ID NO:2, with a dissociation constant <1000 nM and which comprises an antigen-binding site comprising in sequence a variable heavy and light chain region which are at least 80% identical to the variable heavy and light chain regions of:
 i) SEQ ID NO:380 and SEQ ID NO:381; or   ii) SEQ ID NO:161 and SEQ ID NO:276.   
     
     
         228 . The binding molecule of  claim 227 , wherein the antigen-binding site comprises in sequence a variable heavy and light chain region which are at least 85% identical to the variable heavy and light chain regions of:
 i) SEQ ID NO:380 and SEQ ID NO:381; or   ii) SEQ ID NO:161 and SEQ ID NO:276.   
     
     
         229 . The binding molecule of  claim 228 , wherein the antigen-binding site comprises in sequence a variable heavy and light chain region which are at least 90% identical to the variable heavy and light chain regions of:
 i) SEQ ID NO:380 and SEQ ID NO:381; or   ii) SEQ ID NO:161 and SEQ ID NO:276.   
     
     
         230 . The binding molecule of  claim 229 , wherein the antigen-binding site comprises in sequence a variable heavy and light chain region which are at least 95% identical to the variable heavy and light chain regions of:
 i) SEQ ID NO:380 and SEQ ID NO:381; or   ii) SEQ ID NO:161 and SEQ ID NO:276.   
     
     
         231 . An isolated monoclonal antibody or antigen-binding fragment thereof that can specifically bind to the same Sp35 epitope as a reference antibody comprising a VH region comprising the amino acids of SEQ ID NO:372, and a VL region comprising the amino acids of SEQ ID NO:373. 
     
     
         232 . The antibody or antigen-binding fragment thereof of  claim 231 , further comprising a heterologous polypeptide fused thereto. 
     
     
         233 . The antibody or antigen-binding fragment thereof of  claim 231 , wherein the antibody or antigen-binding fragment thereof is conjugated to an agent selected from the group consisting of a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a virus, a lipid, a biological response modifier, a pharmaceutical agent, and polyethylene glycol (PEG). 
     
     
         234 . A composition comprising the antibody or antigen-binding fragment thereof of  claim 231 , and a carrier. 
     
     
         235 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 231 , and a pharmaceutically acceptable carrier. 
     
     
         236 . The antibody or antigen-binding fragment thereof of  claim 231 , wherein the antibody or antigen-binding fragment thereof comprises a brain targeting moiety. 
     
     
         237 . The antibody or antigen-binding fragment thereof of  claim 236 , wherein the brain targeting moiety is selected from the group consisting of FC5, mAB 83-14, OX26, B2, B6, and B8 polypeptides, an anti-Fc receptor antibody, transferrin, an anti-transferrin receptor antibody, and an anti-insulin receptor antibody. 
     
     
         238 . A method of treating multiple sclerosis in a human subject in need thereof, the method comprising administering to the subject an effective amount of the antibody or antigen-binding fragment thereof of  claim 231 . 
     
     
         239 . A method of promoting myelination in a human subject in need thereof, the method comprising administering to the subject an effective amount of the antibody or antigen-binding fragment thereof of  claim 231 . 
     
     
         240 . A method of treating optic neuritis in a human subject in need thereof, the method comprising administering to the subject an effective amount of the antibody or antigen-binding fragment thereof of  claim 231 . 
     
     
         241 . A method of treating acute ischemic optic neuropathy in a human subject in need thereof, the method comprising administering to the subject an effective amount of the antibody or antigen-binding fragment thereof of  claim 231 .