Monoclonal antibodies targeting amyloid beta oligomers

• US 8,795,664 B2
• Filed: 06/03/2011
• Issued: 08/05/2014
• Est. Priority Date: 06/04/2010
• Status: Active Grant

• Current Assignee: Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts Universitätsmedizin (Georg-August-Universität Göttingen), Synaptic Systems Gesellschaft für neurobiologische Forschung, Entwicklung und Produktion mbH
• Original Assignee: Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts Universitätsmedizin (Georg-August-Universität Göttingen), Synaptic Systems Gesellschaft für neurobiologische Forschung, Entwicklung und Produktion mbH
• Inventors: Martens, Henrik, Erck, Christian, Bayer, Thomas, Wirths, Oliver
• Primary Examiner(s): BALLARD, KIMBERLY
• Application Number:
  US13/701,758
• Publication Number:
  US 20130295095A1
• Time in Patent Office: 1,159 Days
• Field of Search: None
• US Class Current: 424/141.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/32 specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
• 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

Abstract

The invention relates to binding molecules capable of specifically recognizing soluble oligomers of N-terminal truncated Aβ starting with pyroglutamate (AβρE), pharmaceutical compositions comprising same, and their respective therapeutic uses. Particularly, the invention relates to an antibody molecule capable of specifically recognizing Aβ oligomers, wherein said antibody binds and/or detects an epitope as bound and/or detected by antibody PG3-38 9D5H6 as deposited under DSM AC-C3056. Further, the invention provides a method of inhibiting the formation or the seeding effect of said AβρE oligomers, and a method for identifying agents useful in the treatment and/or prevention of an amyloid-related disorder as well as methods of diagnosing a subject suspected of suffering from a disease associated with amyloidogenesis and/or amyloid plaque formation and to methods of monitoring the efficacy of a treatment of a disease associated with amyloidogenesis and/or amyloid-plaque formation characterized by the presence of Aβ oligomers in a subject.

Claims

1. An antibody molecule wherein said antibody molecule is an antibody obtainable by hybridoma as deposited under DSM ACC3056 or hybridoma as deposited under DSM ACC3066 on May 27, 2010 with the DSMZ GmbH, Braunschweig, Germany.

2. The antibody molecule according to claim 1, wherein said antibody molecule is capable of staining blood vessels, or cells, or both in a tissue sample.

3. The antibody molecule according to claim 1, wherein said antibody recognizes a conformational epitope or a discontinuous epitope formed by Aβ

oligomers.

4. A hybridoma which produces the monoclonal antibody according to claim 1, wherein the hybridoma is hybridoma DSM ACC3056 or hybridoma DSM ACC3066 deposited on May 27, 2010 with the DSMZ GmbH, Braunschweig, Germany.

10. A pharmaceutical composition comprising an antibody molecule as defined in claim 1 or claim 5, and a pharmaceutically acceptable carrier, excipient, diluent, or a combination thereof.

11. A diagnostic composition comprising an antibody molecule according to claim 1 or claim 5.

12. A kit comprising an item selected from an antibody molecule according to claim 1 or claim 5, a pharmaceutical composition thereof, and combinations thereof.

5. An isolated antibody molecule, wherein said antibody molecule comprises:

(a) a variable region that comprises a H-CDR1, a H-CDR2 and a H-CDR3 as encoded by the nucleic acid sequence as shown in SEQ ID NOs;

1, 3 and 5; and

a variable region that comprises a L-CDR1, a L-CDR2 and a L-CDR3 as encoded by the nucleic acid sequence as shown in SEQ ID NOs;

7, 9 and 11;

or

(b) a variable region that comprises a H-CDR1, a H-CDR2 and a H-CDR3 as encoded by the nucleic acid sequence as shown in SEQ ID NOs;

13, 15 and 17; and

a variable region that comprises a L-CDR1, a L-CDR2 and a L-CDR3 as encoded by the nucleic acid sequence as shown in SEQ ID NOs;

19, 21 and 23;

or

(c) a heavy chain variable region comprising the three CDRs of SEQ ID NOs;

2, 4 and 6, and a light chain variable region comprising the three CDRs of SEQ ID NOs;

8, 10, and 12;

or

(d) a heavy chain variable region comprising the three CDRs of SEQ ID NOs;

14, 16 and 18, and a light chain variable region comprising the three CDRs of SEQ ID NOs;

20, 22, and 24,

wherein the antibody molecule is a F(ab)-fragment, a F(ab)₂-fragment a F(v)-fragment, a single-chain antibody, a chimeric antibody, a CDR-grafted antibody, a bivalent antibody-construct, a humanized antibody, or a diabody.

6. The antibody molecule of claim 5 (a) or (c), wherein said antibody molecule comprises:

(a) variable regions as encoded by a nucleic acid molecule comprising the nucleic acid molecules of SEQ ID NOs;

25 and 27;

or

(b) variable regions comprising the amino acid sequence of SEQ ID NOs;

26 and 28.

7. The antibody molecule of claim 5 (b) or (d), wherein said antibody molecule comprises:

(a) variable regions as encoded by a nucleic acid molecule comprising the nucleic acid molecules of SEQ ID NOs;

29 and 31;

or

(b) variable regions comprising the amino acid sequence of SEQ ID NOs;

30 and 32.

8. The antibody molecule according to claim 5, wherein said antibody molecule is capable of staining blood vessels, or cells, or both in a tissue sample.

9. The antibody molecule according to claim 5, wherein said antibody recognizes a conformational epitope or a discontinuous epitope formed by Aβ

oligomers.

13. A method of treating an amyloid-related disorder, the method comprising administering a binding molecule to a subject suffering or prone to suffer from said amyloid-related disorder, wherein said binding molecule is an antibody molecule obtainable by the hybridoma deposited with the DSMZ under accession number DSM ACC3056 (antibody 9D5H6) or the hybridoma deposited with the DSMZ under accession number DSM ACC3066 (antibody 8C4D2).

14. The method of claim 13, wherein the binding molecule is capable of inhibiting A6-oligomerization as determined in a thioflavin T aggregation assay.

15. The method of claim 13, wherein said binding molecule inhibits the seeding effect of Aβ

pE3 oligomers.

16. The method of claim 13, wherein said binding molecule recognizes a conformational epitope formed by at least two Aβ

-pE3 peptides forming said soluble Aβ

pE3 oligomers.

17. The method of claim 13, wherein the amyloid-related disorder is selected from Alzheimer disease, cerebral amyloid angiopathy, dementia, motor neuropathy, Down'"'"'s syndrome, Creutzfeld Jacob disease, transmissible spongiform encephalopathies, hereditary cerebral hemorrhage with amyloidosis Dutch type, Parkinson'"'"'s disease, HIV-related dementia, fronto-temporal dementia, Lewy body disease, mixed dementias, head trauma, familial Danish Dementia, familial British Dementia, inclusion body myositis (IBM), or neuronal disorder related to aging.

18. The method of claim 13, wherein the Alzheimer disease is sporadic Alzheimer disease.

19. The method of claim 13, wherein the Alzheimer disease is familial Alzheimer disease.

20. The method of claim 13, wherein the transmissible spongiform encephalopathies is selected from Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia and kuru.

21. The method of claim 13, wherein the binding molecule is an antibody molecule, selected from a monoclonal antibody, a recombinant full antibody (immunoglobulin), a F(ab)-fragment, a F(ab)₂-fragment, a F(v)-fragment, a single-chain antibody, a chimeric antibody, a CDR-grafted antibody, a bivalent antibody-construct, a synthetic antibody, a cross-cloned antibody, a humanized antibody, and a diabody.

22. The method of claim 13, wherein the binding molecule is in the form of a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, excipient, diluent, or a combination thereof.

23. The method of claim 22, wherein the composition is administered to said subject at a dose of 1 ng/kg body weight to 100 mg/kg body weight of said subject.

24. The method of claim 22, wherein the composition is administered via injection.

25. The method of claim 22, wherein the composition is administered directly into cerebral fluid or selected brain regions.

26. A method of inhibiting the formation or the seeding effect of oligomers of Aβ

pE3 associated with an amyloid-related disorder in a subject, who has or is prone to form said oligomers, comprising administering a binding molecule to said subject, wherein said binding molecule is an antibody molecule obtainable by the hybridoma deposited with the DSMZ under accession number DSM ACC3056 (antibody 9D5H6) or the hybridoma deposited with the DSMZ under accession number DSM ACC3066 (antibody 8C4D2).

27. The method of claim 26, wherein said Aβ

pE3 is Aβ

pE(3-X), wherein X is selected from 42, 40, 38, 41, 39, and 37.

28. The method of claim 26, wherein the binding molecule is capable of inhibiting Aβ

-oligomerization as determined in a thioflavin T aggregation assay.

29. The method of claim 26, wherein said binding molecule inhibits the seeding effect of Aβ

pE3 oligomers.

30. The method of claim 26, wherein said binding molecule recognizes a conformational epitope formed by more than one Aβ

-pE3 peptide forming said soluble Aβ

pE3 oligomers.

31. The method of claim 26, wherein the amyloid-related disorder is selected from Alzheimer disease, cerebral amyloid angiopathy, dementia, motor neuropathy, Down'"'"'s syndrome, Creutzfeld Jacob disease, transmissible spongiform encephalopathies, hereditary cerebral hemorrhage with amyloidosis Dutch type, Parkinson'"'"'s disease, HIV-related dementia, fronto-temporal dementia, Lewy body disease, mixed dementias, head trauma, familial Danish Dementia, familial British Dementia, inclusion body myositis (IBM), or neuronal disorder related to aging.

32. The method of claim 26, wherein the Alzheimer disease is sporadic Alzheimer disease.

33. The method of claim 26, wherein the Alzheimer disease is familial Alzheimer disease.

34. The method of claim 26, wherein the transmissible spongiform encephalopathies is selected from Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia and kuru.

35. The method of claim 26, wherein the binding molecule is an antibody molecule, selected from a monoclonal antibody, a recombinant full antibody (immunoglobulin), a F(ab)-fragment, a F(ab)₂-fragment, a F(v)-fragment, a single-chain antibody, a chimeric antibody, a CDR-grafted antibody, a bivalent antibody-construct, a synthetic antibody, a cross-cloned antibody, a humanized antibody, and a diabody.

36. The method of claim 35, wherein the binding molecule is in the form of a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, excipient, diluent, or a combination thereof.

37. The method of claim 36, wherein the composition is administered to said subject at a dose of 1 ng/kg body weight to 100 mg/kg body weight of said subject.

38. The method of claim 36, wherein the composition is administered via injection.

39. The method of claim 36, wherein the composition is administered directly into cerebral fluid or selected brain regions.