Monoclonal antibodies against the rgm a protein for use in the treatment of retinal nerve fiber layer degeneration

Abstract

The present application describes RGM A binding proteins, particularly monoclonal antibodies, and in particular CDR grafted, humanized versions thereof, which have the ability to bind to RGM A and prevent binding of RGM proteins to RGM A receptor and other RGM A binding proteins, and therefore neutralize the function of RGM A, for use in the treatment of retinal nerve fiber layer (RNFL) degeneration as well as methods of therapeutically or prophylactically treating a mammal against RNFL degeneration.

What is claimed is: 
     
         1 . A binding protein for human RGM A for use in the treatment of retinal nerve fiber layer (RNFL) degeneration. 
     
     
         2 . The binding protein for use as defined in  claim 1 , wherein said treatment is an therapeutic or prophylactic, neuroregenerative or neuroprotective, local or systemic treatment. 
     
     
         3 . The binding protein for use as defined in  claim 1 , wherein as a result of said treatment
 a) retinal neuron sprouting is observed; and/or   b) RGC (Retinal Ganglion Cell) axons in the retina are preserved from degeneration.   
     
     
         4 . The binding protein for use as defined in  claim 1 , wherein said RNFL degeneration is associated with a disease selected from:
 diabetic retinopathy, ischemic optic neuropathy, X-chromosome linked retinoschisis, drug-induced optic neuropathy, retinal dystrophy, age-related macula degeneration, eye diseases characterized by optic nerve head drusen, eye disease characterized by genetic determinants of photoreceptor degeneration, autosomal recessive cone-rod dystrophy, and mitochondrial disorders with optic neuropathy.   
     
     
         5 . The binding protein for use as defined in  claim 1  that dissociates from human RGM A with a K D  of 1×10 −7  M or less and a k off  rate constant of 1×10 −2  s −1  or less, both determined by surface plasmon resonance. 
     
     
         6 . The binding protein for use as defined in  claim 1  that binds to human RGM A and neutralizes the neurite outgrowth inhibitory activity of human RGM A as determined in a standard in vitro assay. 
     
     
         7 . The binding protein for use as defined in  claim 1 , which is a humanized antibody. 
     
     
         8 . The binding protein for use as defined in  claim 1 , comprising an antigen binding domain, said binding protein capable of binding an epitope of an RGM molecule, said antigen binding domain comprising at least one CDR selected from the group consisting of:
 a) the CDR-H3 group amino acid sequences consisting of SEQ ID NO: 59 and 65, and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences; and/or   b) the CDR-L3 group amino acid sequences consisting of SEQ ID NO: 62 and 68, and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.   
     
     
         9 . The binding protein for use as defined in  claim 8 , further comprising at least one CDR selected from:
 a) the CDR-H1 group of amino acid sequences consisting of SEQ ID NO: 57 and 63; and/or   b) the CDR-L1 group of amino acid sequences consisting of SEQ ID NO: 60 an 66; and/or   c) the CDR-H2 group of amino acid sequences consisting of SEQ ID NO: 58 and 64; and/or   d) the CDR-L2 group of amino acid sequences consisting of SEQ ID NO: 61 and 67; and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.   
     
     
         10 . The binding protein for use as defined in  claim 9 , comprising at least 3 CDRs which are selected from a variable domain CDR set consisting of: 
       
         
           
                 
                 
                 
               
                     
                 
                   VH 5F9 set 
                     
                     
                 
                   VH 5F9 CDR-H1 
                   Residues 31-35 of SEQ ID NO.: 34 
                   SEQ ID NO: 57 
                 
                   VH 5F9 CDR-H2 
                   Residues 50-66 of SEQ ID NO.: 34 
                   SEQ ID NO: 58 
                 
                   VH 5F9 CDR-H3 
                   Residues 99-104 of 
                   SEQ ID NO: 59 
                 
                     
                   SEQ ID NO.: 34 
                 
                   VL 5F9 set 
                 
                   VL 5F9 CDR-L1 
                   Residues 24-39 of SEQ ID NO.: 10 
                   SEQ ID NO: 60 
                 
                   VL 5F9 CDR-L2 
                   Residues 55-61 of SEQ ID NO.: 10 
                   SEQ ID NO: 61 
                 
                   VL 5F9 CDR-L3 
                   Residues 94-102 
                   SEQ ID NO: 62 
                 
                     
                   of SEQ ID NO.: 10 
                 
                   VH 8D1 set 
                 
                   VH 8D1 CDR-H1 
                   Residues 31-35 of SEQ ID NO.: 55 
                   SEQ ID NO: 63 
                 
                   VH 8D1 CDR-H2 
                   Residues 50-66 of SEQ ID NO.: 55 
                   SEQ ID NO: 64 
                 
                   VH 8D1 CDR-H3 
                   Residues 97-110 of 
                   SEQ ID NO: 65 
                 
                     
                   SEQ ID NO.: 55 
                 
                   VL 8D1 set 
                 
                   VL 8D1 CDR-L1 
                   Residues 24-34 of SEQ ID NO.: 56 
                   SEQ ID NO: 66 
                 
                   VL 8D1 CDR-L2 
                   Residues 50-56 of SEQ ID NO.: 56 
                   SEQ ID NO: 67 
                 
                   VL 8D1 CDR-L3 
                   Residues 89-97 of SEQ ID NO.: 57 
                   SEQ ID NO: 68 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a variable domain set wherein at least one of said 3 CDRs is a modified CDR amino acid sequence having a sequence identity of at least 50% to the parent sequence. 
       
     
     
         11 . The binding protein for use as defined in  claim 10 , comprising at least two variable domain CDR sets. 
     
     
         12 . The binding protein for use as defined in  claim 11 , wherein said at least two variable domain CDR sets are selected from a group consisting of:
 VH 5F9 set& VL 5F9 set; and   VH 8D1 set & VL 8D1 set.   
     
     
         13 . The binding protein for use as defined in  claim 12 , further comprising a human acceptor framework. 
     
     
         14 . The binding protein for use as defined in  claim 1 , comprising at least one heavy chain variable domain selected from SEQ ID NO: 35, 36, 37, 38, 39, 40, 41, 42, and 43; and/or at least one light chain variable domain selected from SEQ ID NO: 44, 45, and 46. 
     
     
         15 . The binding protein for use as defined in  claim 13 , wherein said human acceptor framework comprises at least one framework region amino acid substitution at a key residue, said key residue selected from the group consisting of:
 (heavy chain sequence position): 1, 5, 37, 48, 49, 88, 98;   (light chain sequence position): 2, 4, 41, 51.   
     
     
         16 . The binding protein of  claim 1 , wherein said binding protein comprises at least one (framework mutated) variable domain having an amino acid sequence selected from the groups consisting of:
 (heavy chain sequences) SEQ ID NO: 47, 48, 49, 50; and   (light chain sequences) SEQ ID NO: 51, 52, 53, and 54.   
     
     
         17 . The binding protein for use as defined in  claim 1 , which is an antibody selected from 5F9 and 8D 1. 
     
     
         18 . A method of treating RNFL degeneration, comprising the step of administering to a mammal in need thereof an effective amount of a composition comprising an isolated binding protein as defined in  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein said treatment is an therapeutic or prophylactic, neuroregenerative or neuroprotective, local or systemic treatment.