Mutations that drive vh4 antibody autoreactivity

Abstract

Antibodies exhibiting a specific genetically modified signature associated with certain diseases of the central nervous system, like multiple sclerosis (MS) and clinically isolated syndrome have been identified. These antibodies recognize and bind with certain tissues in the brain and central nervous system and thus are useful as therapeutics, in the production of animal disease models, targets for therapies and as part of assays of the central nervous system.

1 . A recombinant antibody or antigen-binding fragment thereof, wherein the recombinant antibody or fragment binds to an antigen in human brain gray matter that is recognized by a VH4-comprising antibody having a mutation with respect to the germline sequence at codon positions selected from 40 and 81, optionally further containing mutations at 31B, 32, 56, 57, 60, and/or 89. 
     
     
         2 . The recombinant antibody or fragment of  claim 1 , wherein the recombinant antibody or fragment has mutations at both codon position 40 and codon position 81,
 or wherein the recombinant antibody or fragment has mutations at codon position 40,   or wherein the recombinant antibody or fragment has mutations at codon position 81.   
     
     
         3 . The recombinant antibody or fragment of  claim 1 , wherein the recombinant antibody or fragment has a serine at codon position 40. 
     
     
         4 . The recombinant antibody or fragment of  claim 1 , wherein the recombinant antibody or fragment has an asparagine at codon position 81. 
     
     
         5 . The antibody or fragment of  claim 1 , wherein said antibody or fragment has heavy chain CDRs and light chain CDRs selected from Tables 1 and 2. 
     
     
         6 . The antibody or fragment of  claim 1 , wherein said recombinant antibody or fragment is linked to a toxin, a drug or a prodrug. 
     
     
         7 . The antibody or fragment of  claim 1 , wherein said recombinant antibody or fragment is an anti-idiotypic Ab or other disruptive construct. 
     
     
         8 . The antibody or fragment of  claim 1 , wherein said recombinant antibody or fragment is linked to a label. 
     
     
         9 . The antibody or fragment of any one of  claim 8 , wherein said label is a chromophore, fluorophore, chemiluminescent compound, dye, contrast agent, radiolabel. 
     
     
         10 . A method of detecting immune mediated neurological diseases in a subject comprising:
 (a) administering to said subject a recombinant antibody or fragment according to  claim 1 ; and   (b) detecting the localization of said antibody in a neuronal tissue of said subject.   
     
     
         11 . The method of  claim 10 , wherein said subject is a human subject. 
     
     
         12 . The method of  claim 10 , wherein said subject is a non-human mammalian subject. 
     
     
         13 . The method of  claim 10 , wherein said antibody or fragment is conjugated to a label. 
     
     
         14 . The method of  claim 10 , wherein said antibody or fragment is detected by the binding of a labeled secondary argent to said antibody. 
     
     
         15 . The method of  claim 10 , wherein the said label is a chromophore, fluorophore, chemiluminescent compound, dye, contrast agent, radiolabel. 
     
     
         16 - 37 . (canceled) 
     
     
         38 . A method for treating a neurodegenerative disorder in a patient, comprising administering to said patient an agent that reduces binding of the antibody according to  claim 1  to an antigen in human grey matter. 
     
     
         39 . The method of  claim 38 , wherein the agent is identified by contacting the antibody and the antigen in human grey matter in the presence of said agent, and detecting loss of antibody binding to said antigen. 
     
     
         40 . The method of  claim 39 , wherein the agent is an anti-idiotypic antibody, an antibody or antigen-binding portion thereof, a peptide, an aptamer, or a small molecule.