Immunological treatment of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Abstract

The present invention relates to an anti-Notch 3 antibody therapy useful for treatment of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. In particular, the invention relates to an anti-Notch3 antibody or a fragment thereof having a 2 fold, 4 fold or 10 fold higher affinity to Notch 3 than to Notch 1 or Notch 2 for use in therapy.

1 . A method of preventing or treating inward remodelling and reduced myogenic tone of brain arteries in a subject in need thereof comprising
 administering to the subject an effective amount of an anti-Notch3 antibody or a fragment thereof having a 2 fold, 4 fold or 10 fold higher affinity to Notch 3 than to Notch 1 or Notch 2.   
     
     
         2 . The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof is binds to a Notch3ECD deposit and/or Wild Type Notch3ECD. 
     
     
         3 . The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof does not bind Notch 1 or Notch 2. 
     
     
         4 . The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof binds to an epitope comprising amino acids 40-1643 of human Notch3 (SEQ ID NO: 3). 
     
     
         5 . The method according to  claim 4  wherein said anti-Notch3 antibody or fragment thereof binds to an epitope comprised in amino acids 657-846 of human Notch3 (SEQ ID NO 7). 
     
     
         6 . The method according to  claim 1 ., wherein said anti-Notch3 antibody or fragment thereof is isolated. 
     
     
         7 . (canceled) 
     
     
         8 . The method according to  claim 1 , wherein the anti-Notch3 antibody or fragment thereof comprises all of
 a heavy chain variable region H-CDR1 comprising SEQ ID NO: 8   a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9   a heavy chain variable region H-CDR3 comprising SEQ ID NO: 10   a light chain variable region L-CDR1 comprising SEQ ID NO:12   a light chain variable region L-CDR2 comprising SEQ ID NO: 13 and   a light chain variable region L-CDR3 comprising SEQ ID NO:14.   
     
     
         9 - 10 . (canceled) 
     
     
         11 . The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof comprises both a heavy chain variable region comprising SEQ ID NO: 11 and a light chain variable domain comprising SEQ ID NO: 15. 
     
     
         12 . The method according to  claim 1 , wherein said anti-Notch3 antibody or fragment thereof is humanized. 
     
     
         13 . A method of eliciting antibodies capable of binding a Notch3ECD deposit in a subject in need thereof, comprising,
 administering to the subject an effective amount of a vaccine comprising:   (A) amino acids 40-1643 of human Notch3 (SEQ ID NO: 3) or a fragment thereof;   (B) amino acids 657-846 of human Notch3 (SEQ ID NO 7) or a fragment thereof; or   (C) (A) and (B).   
     
     
         14 . The method according to  claim 6   13 , wherein said vaccine further comprising comprises an adjuvant. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 13 , wherein the treatment is chronic. 
     
     
         17 . The method of  claim 16 , wherein the chronic treatment is for at least: 2 weeks, 1 month, 6 months, or 1 year. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The method according to  claim 1 , wherein the treatment is chronic. 
     
     
         21 . The method according to  claim 20 , wherein the chronic treatment is for at least: 2 weeks, 1 month, 6 months, or 1 year. 
     
     
         22 . A pharmaceutical composition comprising
 i) an anti-Notch3 antibody or a fragment thereof having a 2 fold, 4 fold or 10 fold higher affinity to Notch 3 than to Notch 1 or Notch 2; or   ii) a vaccine comprising:   (A) amino acids 40-1643 of human Notch3 (SEQ ID NO: 3) or a fragment thereof;   (B) amino acids 657-846 of human Notch3 (SEQ ID NO 7) or a fragment thereof; or   (C) (A) and (B).   
     
     
         23 . A The pharmaceutical composition according to  claim 22  wherein the anti-Notch3 antibody or fragment thereof is labelled. 
     
     
         24 . A composition comprising
 i) an anti-Notch3 antibody or a fragment thereof having a 2 fold, 4 fold or 10 fold higher affinity to Notch 3 than to Notch 1 or Notch 2, and a physiologically acceptable carrier; or   ii) (A) amino acids 40-1643 of human Notch3 (SEQ ID NO: 3) or a fragment thereof;
 (B) amino acids 657-846 of human Notch3 (SEQ ID NO 7) or a fragment thereof; or 
 (C) (A) and (B); 
   and a physiologically acceptable carrier.   
     
     
         25 . The method of  claim 1 , wherein the subject suffers from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). 
     
     
         26 . A vaccine comprising:
 (A) amino acids 40-1643 of human Notch3 (SEQ ID NO: 3) or a fragment thereof;   (B) amino acids 657-846 of human Notch3 (SEQ ID NO 7) or a fragment thereof; or   (C) (A) and (B).   
     
     
         27 . The vaccine according to  claim 26 , wherein said vaccine further comprises an adjuvant.