Antibodies that specifically bind to A beta oligomers and use thereof

• US 9,090,679 B2
• Filed: 04/16/2010
• Issued: 07/28/2015
• Est. Priority Date: 04/17/2009
• Status: Active Grant

• Current Assignee: Immunas Pharma, Inc. (Oncotherapy Science, Inc.)
• Original Assignee: Immunas Pharma, Inc. (Oncotherapy Science, Inc.)
• Inventors: Yokoseki, Tatsuki, Okamoto, Yasuhide, Umeda, Makoto, Ito, Toshiyuki, Imai, Yukiho, Fujii, Shinobu, Takamatsu, Naofumi
• Primary Examiner(s): Goddard, Laura B
• Assistant Examiner(s): Natarajan, Meera
• Application Number:
  US13/264,671
• Publication Number:
  US 20120082667A1
• Time in Patent Office: 1,929 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/4709 Amyloid plaque core protein
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

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.

Claims

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.