Antibodies that specifically bind to A beta oligomers and use thereof
The present inventors successfully produced monoclonal antibodies that are specific to only soluble A beta oligomers, but do not recognize soluble A beta 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 that recognizes an isolated A beta (Aβ) tetramer as an antigen, wherein the antibody does not bind to an Aβ monomer, and wherein the antibody comprises a heavy chain having CDR1, CDR2, and CDR3, which are identified in heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 594, and a light chain having CDR1, CDR2, and CDR3, which are identified in light chain variable region comprising the amino acid sequence of SEQ ID NO: 596.
2. The antibody of claim 1 , which comprises:
(1) a heavy chain having the amino acid sequence of SEQ ID NO: 262 as CDR1, the amino acid sequence of SEQ ID NO: 264 as CDR2, and the amino acid sequence of SEQ ID NO: 266 as CDR3; or
(2) a light chain having the amino acid sequence of SEQ ID NO: 268 as CDR1, the amino acid sequence of SEQ ID NO: 270 as CDR2, and the amino acid sequence of SEQ ID NO: 272 as CDR3.
3. The antibody of claim 1 , wherein the antibody is a chimeric antibody or a humanized antibody.
4. An antigen-binding fragment of the antibody of claim 1 .
5. A pharmaceutical composition comprising the antibody of claim 1 , and a pharmaceutically acceptable carrier.
6. The composition of claim 5 , which is formulated for administration as an agent against cognitive impairment, a therapeutic agent for Alzheimer's disease, an agent for suppressing the progression of Alzheimer's disease, an agent for suppressing senile plaque formation, an agent for suppressing Aβ accumulation, an anti-neurotoxic agent, an agent for inhibiting Aβ amyloid fibril formation, or an agent against synaptic toxicity.
7. A method for detecting an Aβ oligomer, which comprises:
(a) contacting a sample collected from a subject with the antibody of claim 1 ; and
(b) immunologically detecting the presence of an Aβ oligomer in the sample.
8. A method of diagnosing whether or not a subject is a possible Alzheimer's disease patient, which comprises:
(a) contacting a sample collected from the subject with the antibody of claim 1 ; and
(b) measuring the amount of Aβ oligomer in the sample, wherein the subject is determined to be a possible Alzheimer's disease patient, when the amount measured in (b) is higher than that of a healthy individual.
9. A method of diagnosing whether or not a subject is a possible Alzheimer's disease patient, which comprises:
(a) contacting a sample collected from the subject with the antibody of claim 1 , 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 be a possible Alzheimer's disease patient, when the ratio measured in (b) is higher than that of a healthy individual.
10. The method of claim 7 , wherein the sample is blood or cerebrospinal fluid.
11. A kit for detecting an Aβ oligomer contained in a sample or for diagnosing whether or not a subject is a possible Alzheimer's disease patient, the kit comprising the antibody of claim 1 .
12. The method of claim 8 , wherein the sample is blood or cerebrospinal fluid.
13. The method of claim 9 , wherein the sample is blood or cerebrospinal fluid.