Novel antibody useful in neurological or neurodegenerative disorders

Abstract

The present invention relates to an anti-NMDA antibody or fragment or derivative thereof which is effective in inhibiting the deleterious effects of tissue-type plasminogen activator (t-PA) mediated by N-methyl-D-aspartate (NMDA) receptors and to medical uses, in particular for the treatment of neurological or neurodegenerative disorders, e.g. multiple sclerosis.

1 . An anti-NMDA receptor antibody or a fragment or derivative thereof, wherein said antibody, fragment or derivative
 (a) is capable of binding an epitope comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28,   (b) comprises one or more complementarity determining regions having an amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, 33 and 34, or   (c) comprises one or more complementarity determining regions which have an amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, 33 and 34 which is altered at one or two amino acid positions or which contains an insertion of one or more amino acids, and which are functional equivalents of the corresponding unaltered complementarity determining regions.   
     
     
         2 . An antibody or a fragment or derivative thereof, which is capable of binding to at least a portion of a region of an NMDA receptor that interacts with t-PA and wherein said binding inhibits the interaction between the NMDA receptor and t-PA, whereby at least one function of the NMDA receptor is selectively inhibited. 
     
     
         3 . The antibody according to  claim 1 , which is a monoclonal antibody, or a fragment or derivative thereof. 
     
     
         4 . The antibody, fragment or derivative according to  claim 1 , which has one or more of the following characteristics:
 (a) it comprises a heavy chain framework region sharing a homology or identity of 80% or more with a framework region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 36, 37 and 38 and/or a light chain framework region sharing a homology or identity of 80% or more with a framework region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 39, 40, 41 and 42, or   (b) it shows cross-reactivity with an antibody produced by a deposited hybridoma selected from the group consisting of 15A4B2E5, 15A4B2F3, 15A4B2, 6C9A3, 6C9A3F4 and 6C9A3F6.   
     
     
         5 . The antibody according to  claim 1 , which comprises one or two heavy chain variable regions comprising the amino acid sequence of SEQ ID NO: 43 and/or which comprises one or two light chain variable regions comprising the amino acid sequence of SEQ ID NO:44, or a fragment or derivative thereof showing cross-reactivity with said antibody. 
     
     
         6 . The derivative according to  claim 5 , whose heavy chain variable regions are identical to each other and share a homology or identity of 80% or more over their entire length with a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 43and/or whose light chain variable regions are identical to each other and share a homology or identity of 80% or more over their entire length with a light chain variable region comprising the amino acid sequence of SEQ ID NO: 44. 
     
     
         7 . An antibody produced by a deposited hybridoma selected from the group consisting of 15A4B2E5, 15A4B2F3, 15A4B2, 6C9A3, 6C9A3F4 and 6C9A3F6, or a fragment or derivative thereof, which shows cross-reactivity with said antibody. 
     
     
         8 . A nucleic acid encoding the antibody, fragment or derivative according to  claim 1 . 
     
     
         9 . An expression cassette or vector comprising the nucleic acid according to  claim 8  and a promoter operatively connected with said nucleic acid. 
     
     
         10 . A host cell comprising the nucleic acid according to  claim 8 . 
     
     
         11 . A phamiaceutical composition comprising the antibody, fragment or derivative of according to  claim 1 , and one or more components selected from the group consisting of carriers, solvents, diluents, and excipients. 
     
     
         12 . (canceled) 
     
     
         13 . A method of treatment of a neurological or neurodegenerative disorder comprising
 administering to a patient in need thereof a therapeutically effect amount of the antibody, fragment or derivative of  claim 1 , wherein said therapeutically effect amount is sufficient to treat said neurological or neurodegenerative disorder.   
     
     
         14 . The method according to  claim 12 , wherein the neurological or neurodegenerative disorder is selected form the group consisting of multiple sclerosis, thrombotic disorder, stroke, intracerebral bleedings TIA, epilepsy, temporal lobe epilepsy, amyotrophic lateral sclerosis, brain tumours, Parkinson disease, Alzheimer's disease, brain oedema, CNS complication resulting from parasitic, bacterial, fungal or viral infections, meningitis, encephalitis, traumatic brain injury, spinal cord injury, intracranial lesions, intravertebral lesions, ischemic disorders, and damage of the optic nerve after acute vascular occlusion or in glaucoma.