Immunoglobulins

Abstract

The present invention relates to antibodies to NOGO, pharmaceutical formulations containing such antibodies and the use of such antibodies in the treatment and/or prophylaxis of neurological diseases/disorder.

1 . A heavy chain variable region comprising a third CDR consisting essentially of the amino acid residues GQGY wherein the CDR contains at least one substitution within the GQGY core sequence, the substitutions being selected from the following substitutions: where the G in the first position is replaced by R, I, W or M; the Q in the second position is replaced by D, I, A, L, V or S; the G in the third position is replaced by W, N, Y, S, L or F; and the Y in the fourth position is replaced by W. 
     
     
         2 . A heavy chain variable region as claimed in  claim 1  wherein there is a single substitution to the GQGY sequence to yield one of the following CDR H3: RQGY (SEQ ID NO.75), IQGY (SEQ ID NO.76), MQGY (SEQ ID NO.45), GDGY (SEQ ID NO.77), GIGY (SEQ ID NO.78), GSGY (SEQ ID NO.79), GQNY (SEQ ID NO.80), GQYY (SEQ ID NO.81), GQSY (SEQ ID NO.62), GQLY (SEQ ID NO.82), GQFY (SEQ ID NO.83), GQGW (SEQ ID NO.84), WQGY (SEQ ID NO.86), GAGY (SEQ ID NO.87), GLGY (SEQ ID NO.88), GVGY (SEQ ID NO.89), GQWY (SEQ ID NO.90). 
     
     
         3 . A heavy chain variable region as claimed in  claim 2  wherein the CDR H3 is MQGY or GQSY. 
     
     
         4 . A heavy chain variable region as claimed in  claim 1 , wherein the heavy chain variable region comprises the sequence SYWMH as CDR H1 (SEQ ID NO. 1) and NINPSNGGTNYNEKFKS as CDR H2 (SEQ ID NO.2). 
     
     
         5 . A heavy chain variable region as claimed in  claim 1 , wherein the heavy chain variable region is a humanised sequence. 
     
     
         6 . A heavy chain variable region as claimed in  claim 5  wherein the acceptor heavy chain variable region sequence has at least 40% identity in the framework regions to the 2A10 donor antibody heavy chain variable region sequence given in SEQ ID NO.7. 
     
     
         7 . A heavy chain variable region as claimed in  claim 6  wherein the heavy chain variable region has an amino acid sequence of SEQ ID NO. 66 (H98 variable region) or SEQ ID NO. 61 (H99 variable region), further comprising a number of substitutions at one or more of numerical positions 38, 40, 67, 68, 70, 72, 74, and 79; wherein each substituted amino acid residue is replaced with the amino acid residue at the equivalent position in SEQ ID NO 7. 
     
     
         8 . A heavy chain variable region as claimed in  claim 1 , having the amino acid sequence given in SEQ ID NO.47 (H26), SEQ ID NO.48 (H27), SEQ ID NO.49 (H28), SEQ ID NO. 63 (H100), SEQ ID NO. 54 (H101), SEQ ID NO. 65 (H102). 
     
     
         9 . An isolated antibody, or fragment thereof, capable of binding to human NOGO-A comprising a heavy chain variable region as claimed in  claim 1  and a light chain variable region. 
     
     
         10 . An isolated antibody or fragment thereof as claimed in  claim 7  comprising the following heavy and light chain variable region pairs: H27L16 (SEQ ID NO.48+SEQ ID NO.14), H28L13 (SEQ ID NO.49+SEQ ID NO.13), H28L16 (SEQ ID NO.49+SEQ ID NO.14). 
     
     
         11 . An isolated antibody as claimed in  claim 9  comprising the following heavy and light chain sequences H27FL L16FL (SEQ ID NO. 54+SEQ ID NO.18), H28FL L13FL (SEQ ID NO. 55+SEQ ID NO.17), H28FL L16FL (SEQ ID NO. 55+SEQ ID NO.18). 
     
     
         12 . A pharmaceutical composition comprising an anti-NOGO antibody or fragment thereof comprising the antibodies or fragments thereof as claimed in  claim 9 , together with a pharmaceutically acceptable diluent or carrier. 
     
     
         13 . Use of an anti-NOGO antibody or fragment thereof as claimed in  claim 9 , in the preparation of a medicament for treatment or prophylaxis of stroke and other neurological diseases/disorders or for the treatment of a patient suffering from a mechanical trauma to the central or peripheral nervous system. 
     
     
         14 . A method for the treatment or prophylaxis of stroke or other neurological disease/disorder or for the treatment of a patient suffering from a mechanical trauma to the central or peripheral nervous system, in a human comprising the step of parenteral administration of a therapeutically effective amount of an anti-NOGO antibody or fragment thereof as claimed in  claim 9 . 
     
     
         15 . An antibody or fragment thereof that is capable of binding to a region of human NOGO protein consisting of the polypeptide sequence of VLPDIVMEAPLN (SEQ ID NO. 60), characterised in that the antibody, or fragment thereof is not an antibody comprising a variable heavy domain having CDR H3 consisting of the amino acid residues GQGY or analogues thereof having one amino acid substitution therein. 
     
     
         16 . (canceled) 
     
     
         17 . An antibody, or fragment thereof, that is capable of binding to human NOGO protein in an ELISA assay, wherein the binding of the antibody, or fragment thereof, to human NOGO protein is reduced in the presence of a peptide having the following sequence VLPDIVMEAPLN (SEQ ID NO. 60), and is not reduced in the presence of an irrelevant peptide, characterised in that the antibody or fragment thereof is not an antibody comprising a heavy chain variable domain having a CDR H3 consisting of the amino acid residues GQGY or analogues thereof having one amino acid substitution therein.