LINGO Binding Molecules and Pharmaceutical Use Thereof

Abstract

The present invention provides a binding molecule which is capable of binding to the rat, cynomolgus monkey and human LINGO polypeptide, a polynucleotide encoding such binding molecule; an expression vector comprising said polynucleotide; an expression system comprising a polynucleotide capable of producing a binding molecule; an isolated host cell which comprises an expression system as defined above; the use of such binding molecule as a pharmaceutical, especially in the treatment to promote axonal regeneration/plasticity; a pharmaceutical composition comprising said binding molecule; and a method of treatment of diseases associated with axonal degeneration and demyelination.

1 . A binding molecule which is capable of binding to the protein according to SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, with a dissociation constant <1000 nM. 
     
     
         2 . A binding molecule according to  claim 1  which binds to one or more of the sequences chosen form the group consisting of SEQ ID NO: 46-51. 
     
     
         3 . A binding molecule according to  claim 1  which is capable of disinhibiting spinal cord myelin at a concentration of less than 20 nM. 
     
     
         4 . A binding molecule according to  claim 1  which is capable of increasing the mean neurite length per cell of rat cerebellar granule cells grown on a substrate of adult rat spinal cord myelin by at least 20%. 
     
     
         5 . A binding molecule according to  claim 1 , which comprises one or more amino acid sequences chosen from the group consisting of SEQ ID NO: 12-17 or SEQ ID NO: 18-23. 
     
     
         6 . A binding molecule according to  claim 5 , which comprises at least one antigen binding site chosen from the group consisting of;
 a sequence which is at least 50% homologous to SEQ ID NO: 5 or SEQ ID NO: 7, and;   a sequence which is at least 50% homologous to SEQ ID NO: 4 or SEQ ID NO: 6, or a direct equivalent thereof.   
     
     
         7 . A binding molecule according to  claim 6 , which comprises a first sequence which is at least 50% homologous to SEQ ID NO: 5 or SEQ ID NO: 7, and a second sequence which is at least 50% homologous to SEQ ID NO: 4 or SEQ ID NO: 6, or a direct equivalent thereof. 
     
     
         8 . The binding molecule according to  claim 5  which comprises at least
 a) one immunoglobulin heavy chain or fragment thereof which comprises 
 (i) a variable domain comprising SEQ ID NO: 5 or SEQ ID NO: 7, and 
 (ii) the constant part or fragment thereof of a human heavy chain; and 
 b) one immunoglobulin light chain or fragment thereof which comprises 
 (i) a variable domain comprising SEQ ID NO: 4 or SEQ ID NO: 6, and 
 (ii) the constant part or fragment thereof of a human light chain; or 
 direct equivalents thereof. 
 
     
     
         9 . A binding molecule according to  claim 5 , which is an antibody or a fragment thereof, or a direct equivalent thereof. 
     
     
         10 . The binding molecule according to  claim 9  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. 
     
     
         11 . The binding molecule according to  claim 9 , which is a human or chimeric or humanized monoclonal antibody. 
     
     
         12 . A polynucleotide encoding a binding molecule according to  claim 9 . 
     
     
         13 . A polynucleotide chosen from the group consisting of SEQ ID NO: 8 and SEQ ID NO: 9; or from the group consisting of SEQ ID NO: 10 and SEQ ID NO: 11. 
     
     
         14 . An expression vector comprising one or more polynucleotides according to  claim 12 . 
     
     
         15 . An expression system comprising a polynucleotide according to  claim 12 , when said expression system or part thereof is present in a compatible host cell. 
     
     
         16 . An isolated host cell which comprises an expression system according to  claim 15 . 
     
     
         17 . A pharmaceutical composition comprising a binding molecule according to  claim 1  together with at least one pharmaceutically acceptable carrier or diluent. 
     
     
         18 . A method of treatment of diseases associated with the promotion of axonal regeneration/plasticity comprising administering to a subject in need of such treatment an effective amount of a binding molecule according to  claim 1 .