Nucleic acid molecules encoding anti-amyloid-beta antibodies

Abstract

The present invention is related to methods and compositions for the therapeutic and diagnostic use in the treatment of diseases and disorders which are caused by or associated with amyloid or amyloid-like proteins including amyloidosis, a group of disorders and abnormalities associated with amyloid protein such as Alzheimer's disease. The present invention provides novel methods and compositions comprising highly specific and highly effective antibodies having the ability to specifically recognize and bind to specific epitopes from a range of β-amyloid proteins. The antibodies enabled by the teaching of the present invention are particularly useful for the treatment of diseases and disorders which are caused by or associated with amyloid or amyloid-like proteins including amyloidosis, a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis including, but not limited to, neurological disorders such as Alzheimer's Disease (AD).

1 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding the light chain variable region of an antibody, or a fragment thereof, which antibody specifically binds to monomeric, oligomeric or polymeric forms of amyloid-β, wherein:
 (i) complementarity determining region 1 (CDR1) of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:23; 
 (ii) CDR2 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:24; and 
 (iii) CDR3 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:25. 
 
     
     
         2 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding the heavy chain variable region of an antibody, or a fragment thereof, which antibody specifically binds to monomeric, oligomeric or polymeric forms of amyloid-β, wherein:
 (i) CDR1 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:26; 
 (ii) CDR2 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:27; and 
 (iii) CDR3 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:28. 
 
     
     
         3 . The nucleic acid molecule of  claim 1  wherein the nucleotide sequence encodes the light chain variable region of SEQ ID NO:7. 
     
     
         4 . The nucleic acid molecule of  claim 1 , wherein the nucleotide sequence is SEQ ID NO: 9. 
     
     
         5 . The nucleic acid molecule of  claim 2  wherein the nucleotide sequence encodes the heavy chain variable region of SEQ ID NO:8. 
     
     
         6 . The nucleic acid molecule of  claim 2 , wherein the nucleotide sequence is SEQ ID NO:11. 
     
     
         7 . A host cell comprising the nucleic acid molecule of  claim 1 . 
     
     
         8 . A host cell comprising the nucleic acid molecule of  claim 2 . 
     
     
         9 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding the light chain variable region or the heavy chain variable region of an antibody, or a fragment thereof, which antibody specifically binds to monomeric, oligomeric or polymeric forms of amyloid-β, wherein:
 (i) CDR1 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:23; 
 (ii) CDR2 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:24; 
 (iii) CDR3 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:25. 
 (iv) CDR1 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:26; 
 (v) CDR2 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:27; and 
 (vi) CDR3 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:28. 
 
     
     
         10 . The nucleic acid molecule of  claim 9  encoding the monoclonal antibody produced by the hybridoma cell line FP 12H3-C2, deposited as DSM ACC2750. 
     
     
         11 . The nucleic acid molecule of  claim 9 , wherein the antibody is a monoclonal antibody. 
     
     
         12 . The nucleic acid molecule of  claim 9 , wherein the nucleotide sequence encodes the light chain variable region of SEQ ID NO:7. 
     
     
         13 . The nucleic acid molecule of  claim 9 , wherein the nucleotide sequence encodes the heavy chain variable region of SEQ ID NO:8. 
     
     
         14 . The nucleic acid molecule of  claim 9 , wherein the nucleotide sequence encodes the light chain variable region of SEQ ID NO:7 and the heavy chain variable region of SEQ ID NO:8. 
     
     
         15 . The nucleic acid molecule of  claim 9 , wherein the nucleotide sequence is SEQ ID NO: 9. 
     
     
         16 . The nucleic acid molecule of  claim 9 , wherein the nucleotide sequence is SEQ ID NO:11. 
     
     
         17 . The nucleic acid molecule of  claim 9 , wherein the nucleotide sequence is SEQ ID NO: 9 and SEQ ID NO:11. 
     
     
         18 . The nucleic acid molecule of  claim 1 , wherein:
 (i) CDR1 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:26;   (ii) CDR2 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:27; and   (iii) CDR3 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:28.   
     
     
         19 . The nucleic acid molecule of  claim 2 , wherein:
 (i) CDR1 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:23;   (ii) CDR2 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:24; and   (iii) CDR3 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:25.   
     
     
         20 . A vector comprising the nucleic acid molecule of  claim 1 . 
     
     
         21 . A vector comprising the nucleic acid molecule of  claim 2 . 
     
     
         22 . A vector comprising the nucleic acid molecule of  claim 9 . 
     
     
         23 . A host cell comprising the nucleic acid molecule of  claim 9 . 
     
     
         24 . The host cell of  claim 23 , wherein the host cell is a bacterial cell, insect cell or mammalian cell. 
     
     
         25 . The host cell of  claim 7 , wherein the host cell is a bacterial cell, insect cell or mammalian cell. 
     
     
         26 . The host cell of  claim 8 , wherein the host cell is a bacterial cell, insect cell or mammalian cell. 
     
     
         27 . A method for producing an antibody which specifically binds to monomeric, oligomeric or polymeric forms of amyloid-β, comprising culturing the host cell of  claim 23 . 
     
     
         28 . A method for producing an antibody which specifically binds to monomeric, oligomeric or polymeric forms of amyloid-β, comprising culturing the host cell of  claim 7 . 
     
     
         29 . A method for producing an antibody which specifically binds to monomeric, oligomeric or polymeric forms of amyloid-β, comprising culturing the host cell of  claim 8 . 
     
     
         30 . A method of producing an antibody or a functional fragment thereof, which antibody specifically binds to monomeric, oligomeric or polymeric forms of amyloid-β, comprising expressing in a cell a polynucleotide comprising:
 a nucleotide sequence encoding the light chain variable region of an antibody, or a fragment thereof, wherein:
 (i) CDR1 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:231; 
 (ii) CDR2 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:24; and 
 (iii) CDR3 of the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:25; 
 
 a nucleotide sequence encoding the heavy chain variable region of an antibody, or a fragment thereof, wherein
 (iv) CDR1 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:26; 
 (v) CDR2 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:27; and 
 (vi) CDR3 of the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:28; 
 
 or a combination thereof.