Antibody Capable of Binding Specifically to AB-Oligomer, and Use Thereof

Abstract

The present inventors successfully produced monoclonal antibodies that are specific to only soluble Aβ oligomers, but do not recognize soluble Aβ monomers, which are physiological molecules. It was demonstrated that the antibodies are useful as diagnostic/therapeutic monoclonal antibodies for Alzheimer's disease.

1 . An antibody binding to an Aβ oligomer that binds to an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 1 and an L chain having the amino acid sequence of SEQ ID NO: 3. 
     
     
         2 . An antibody binding to an Aβ oligomer that binds to an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 21 and an L chain having the amino acid sequence of SEQ ID NO: 23. 
     
     
         3 . An antibody binding to an Aβ oligomer that binds to an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 41 and an L chain having the amino acid sequence of SEQ ID NO: 43. 
     
     
         4 . An antibody binding to an Aβ oligomer that binds to an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 61 and an L chain having the amino acid sequence of SEQ ID NO: 63. 
     
     
         5 . An antibody binding to an Aβ oligomer that binds to an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 81 and an L chain having the amino acid sequence of SEQ ID NO: 83. 
     
     
         6 . An antibody binding to an Aβ oligomer that binds to an antibody comprising an H chain having the amino acid sequence of SEQ ID NO: 101 and an L chain having the amino acid sequence of SEQ ID NO: 103. 
     
     
         7 . An antibody of any one of (1) to (38) below:
 (1) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 9 as CDR1, the amino acid sequence of SEQ ID NO: 11 as CDR2, and the amino acid sequence of SEQ ID NO: 13 as CDR3;   (2) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 15 as CDR1, the amino acid sequence of SEQ ID NO: 17 as CDR2, and the amino acid sequence of SEQ ID NO: 19 as CDR3;   (3) an antibody that comprises the H chain of (1) and the L chain of (2);   (4) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 5 as VH;   (5) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 7 as VL;   (6) an antibody that comprises the H chain of (4) and the L chain of (5);   (7) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 29 as CDR1, the amino acid sequence of SEQ ID NO: 31 as CDR2, and the amino acid sequence of SEQ ID NO: 33 as CDR3;   (8) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 35 as CDR1, the amino acid sequence of SEQ ID NO: 37 as CDR2, and the amino acid sequence of SEQ ID NO: 39 as CDR3;   (9) an antibody that comprises the H chain of (7) and the L chain of (8);   (10) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 25 as VH;   (11) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 27 as VL;   (12) an antibody that comprises the H chain of (10) and the L chain of (11);   (13) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 49 as CDR1, the amino acid sequence of SEQ ID NO: 51 as CDR2, and the amino acid sequence of SEQ ID NO: 53 as CDR3;   (14) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 55 as CDR1, the amino acid sequence of SEQ ID NO: 57 as CDR2, and the amino acid sequence of SEQ ID NO: 59 as CDR3;   (15) an antibody that comprises the H chain of (13) and the L chain of (14);   (16) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 45 as VH;   (17) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 47 as VL;   (18) an antibody that comprises the H chain of (16) and the L chain of (17);   (19) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 69 as CDR1, the amino acid sequence of SEQ ID NO: 71 as CDR2, and the amino acid sequence of SEQ ID NO: 73 as CDR3;   (20) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 75 as CDR1, the amino acid sequence of SEQ ID NO: 77 as CDR2, and the amino acid sequence of SEQ ID NO: 79 as CDR3;   (21) an antibody that comprises the H chain of (19) and the L chain of (20);   (22) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 65 as VH;   (23) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 67 as VL;   (24) an antibody that comprises the H chain of (22) and the L chain of (23);   (25) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 89 as CDR1, the amino acid sequence of SEQ ID NO: 91 as CDR2, and the amino acid sequence of SEQ ID NO: 93 as CDR3;   (26) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 95 as CDR1, the amino acid sequence of SEQ ID NO: 97 as CDR2, and the amino acid sequence of SEQ ID NO: 99 as CDR3;   (27) an antibody that comprises the H chain of (25) and the L chain of (26);   (28) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 85 as VH;   (29) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 87 as VL;   (30) an antibody that comprises the H chain of (28) and the L chain of (29);   (31) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 109 as CDR1, the amino acid sequence of SEQ ID NO: 111 as CDR2, and the amino acid sequence of SEQ ID NO: 113 as CDR3;   (32) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 115 as CDR1, the amino acid sequence of SEQ ID NO: 117 as CDR2, and the amino acid sequence of SEQ ID NO: 119 as CDR3;   (33) an antibody that comprises the H chain of (31) and the L chain of (32);   (34) an antibody that comprises an H chain having the amino acid sequence of SEQ ID NO: 105 as VH;   (35) an antibody that comprises an L chain having the amino acid sequence of SEQ ID NO: 107 as VL;   (36) an antibody that comprises the H chain of (34) and the L chain of (35);   (37) an antibody that comprises one or more amino acid substitutions, deletions, additions, and/or insertions in the antibody of any one of (1) to (36), which has equivalent activity to the antibody of any one of (1) to (36); and   (38) an antibody that binds to the epitope bound by the antibody of any one of (1) to (36).   
     
     
         8 . The antibody of  claim 7 , wherein the antibody is a chimeric antibody or a humanized antibody. 
     
     
         9 . A composition comprising the antibody of any one of  claims 1  to  7  and a pharmaceutically acceptable carrier. 
     
     
         10 . A method for preventing and/or treating cognitive impairment, which comprises administering the antibody of any one of  claims 1  to  7  as an active ingredient. 
     
     
         11 . A method for preventing and/or treating Alzheimer's disease, which comprises administering the antibody of any one of  claims 1  to  7  as an active ingredient. 
     
     
         12 . A method for suppressing the progression of Alzheimer's disease, which comprises administering the antibody of any one of  claims 1  to  7  as an active ingredient. 
     
     
         13 . A method for suppressing senile plaque formation, which comprises administering the antibody of any one of  claims 1  to  7  as an active ingredient. 
     
     
         14 . A method for suppressing Aβ accumulation, which comprises administering the antibody of any one of  claims 1  to  7  as an active ingredient. 
     
     
         15 . A method for neutralizing neurotoxicity, which comprises administering the antibody of any one of  claims 1  to  7  as an active ingredient. 
     
     
         16 . A method for inhibiting Aβ amyloid fibril formation, which comprises administering the antibody of any one of  claims 1  to  7  as an active ingredient. 
     
     
         17 . A method for neutralizing synaptic toxicity, which comprises administering the antibody of any one of  claims 1  to  7  as an active ingredient. 
     
     
         18 . A method for detecting an Aβ oligomer, which comprises detecting an Aβ oligomer contained in a sample collected from a subject using the antibody of any one of  claims 1  to  7 . 
     
     
         19 . The method of  claim 18 , wherein the sample is blood or cerebrospinal fluid. 
     
     
         20 . A method of diagnosing whether or not a subject suffers from or is at a risk of developing Alzheimer's disease, which comprises using the antibody of any one of  claims 1  to  7  to detect an Aβ oligomer in a sample collected from a subject. 
     
     
         21 . A method of diagnosing whether or not a subject suffers from or is at a risk of developing Alzheimer's disease, which comprises:
 (a) contacting a sample collected from a subject with the antibody of any one of  claims 1  to  7 ; and   (b) measuring the amount of Aβ oligomer in the sample,   
       wherein the subject is determined to suffer from or be at a risk of developing Alzheimer's disease, when the amount measured in (b) is higher than that of a healthy individual. 
     
     
         22 . A method of diagnosing whether or not a subject suffers from or is at a risk of developing Alzheimer's disease, which comprises:
 (a) contacting a sample collected from a subject with the antibody of any one of  claims 1  to  7  and an antibody that binds to an Aβ monomer; and   (b) measuring the ratio of Aβ oligomer to Aβ monomer in the sample,   
       wherein the subject is determined to suffer from or be at a risk of developing Alzheimer's disease, when the ratio measured in (b) is higher than that of a healthy individual. 
     
     
         23 . The method of  claim 20 , wherein the sample is blood or cerebrospinal fluid.