Antibodies directed against amyloid-beta peptide and methods using same

• US 20060292152A1
• Filed: 04/28/2006
• Published: 12/28/2006
• Est. Priority Date: 04/29/2005
• Status: Active Grant

• Current Assignee: Rinat Neuroscience Corp. (Pfizer Inc.)
• Original Assignee: Rinat Neuroscience Corp. (Pfizer Inc.)
• Inventors: Rosenthal, Arnon, Pons, Jaume, Ho, Wei-Hsien
• Granted Patent: US 7,763,250 B2
• Time in Patent Office: Days
• US Class Current: 424/146.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 31/18 for HIV
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/522 CH1 domain
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Antibodies directed to the C-terminal side of β-amyloid peptide and methods of using these antibodies for diagnosing and treatment of Alzheimer'"'"'s disease and Aβ peptide associated diseases are described.

Claims

1. A monoclonal antibody that specifically binds to an Aβ

peptide, wherein the antibody binds to an epitope on Aβ

_1-40 that includes amino acids 25-34 and 40, wherein the antibody binds to Aβ

_1-40 with higher affinity than its binding to Aβ

_1-42 and Aβ

_1-43, and wherein the antibody is not antibody 2294.

2. The antibody of claim 1, wherein the antibody binds to Aβ

_1-40 with at least about 40-fold higher affinity than its binding to Aβ

_1-42 or Aβ

_1-43.

3. The antibody of claim 1, wherein the Fab fragment of the antibody binds Aβ

_1-40 with an affinity of about 5 nM or less.

4. The antibody of claim 1, wherein the isotype of the antibody is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

5. The antibody of claim 1, wherein the antibody comprises a heavy chain constant region comprising a Fc region, wherein the heavy chain constant region has impaired effector function.

6. The antibody of claim 5, wherein N-glycosylation in the Fc region is removed.

7. The antibody of claim 5, wherein the heavy chain constant region of the antibody is a human IgG2a constant region comprising amino acid mutations A330P331 to S330S331, wherein the amino acid position is based on Kabat numbering with reference to human wildtype IgG2a sequence.

8. The antibody of claim 5, wherein the heavy chain constant region of the antibody is a human IgG4 constant region comprising amino acid mutations from E233F234L235 to P233V234A235, wherein the amino acid position is based on Kabat numbering with reference to human wildtype IgG4 sequence.

9. The antibody of claim 1, wherein the antibody is a human antibody.

10. The antibody of claim 1, wherein the antibody is a humanized antibody.

11. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising three CDRs from heavy chain variable region of an antibody shown in Table 3, and a light chain variable region comprising three CDRs from light chain variable region of an antibody shown in Table 3.

12. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising three CDRs from antibody 6G heavy chain variable region shown in SEQ ID NO:

1, and a light chain variable region comprising three CDRs from antibody 6G light variable region shown in SEQ ID NO;

2.

13. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising the three CDRs shown in SEQ ID NO:

3, SEQ ID NO;

4, and SEQ ID NO;

5, and a light chain variable region comprising the three CDRs shown in SEQ ID NO;

6, SEQ ID NO;

7, and SEQ ID NO;

8.

14. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:

1, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO;

2.

15. The antibody of claim 1, wherein the antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO:

11, and the light chain amino acid sequence shown in SEQ ID NO;

12.

24. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.

25. A polynucleotide comprising a nucleotide sequence encoding the antibody of claim 1.

26. The polynucleotide of claim 25, wherein the polynucleotide comprises the nucleotide sequence of SEQ ID NOS:

13 and 14.

30. A vector comprising the polynucleotide of claim 25.

36. A host cell comprising the polynucleotide of claim 25.

40. A method of producing an antibody, comprising culturing the host cell of claim 36 under conditions such that the antibody is produced;

and isolating the antibody from the host cell or culture.

41. A method for treating Alzheimer'"'"'s disease in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of claim 24.

42. A method of suppressing formation of amyloid plaques in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of claim 24.

43. A method of reducing amyloid plaques in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of claim 24.

44. A method of delaying development of a symptom associated with Alzheimer'"'"'s disease in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of claim 24.

16. An antibody heavy chain comprising three CDRs from heavy chain of an antibody shown in Table 3.

17. The antibody heavy chain of claim 16, wherein the three CDRs are from antibody 6G heavy chain variable region shown in SEQ ID NO:

1.

18. The antibody heavy chain of claim 16, wherein the heavy chain comprises the amino acid sequence shown in SEQ ID NO:

1.

27. A polynucleotide comprising a nucleotide sequence encoding the heavy chain of claim 16.

31. A vector comprising the polynucleotide of claim 27.

32. The vector of claim 31, wherein the vector is pDb.6G.hFc2a with a deposit number of ATCC No. PTA-6786.

37. A host cell comprising the polynucleotide of claim 27.

19. An antibody light chain comprising three CDRs from light chain of an antibody shown in Table 3.

20. The antibody light chain of claim 19, wherein the three CDRs are from antibody 6G light chain variable region shown in SEQ ID NO:

2.

21. The antibody light chain of claim 19, wherein the light chain comprises the amino acid sequence shown in SEQ ID NO:

2.

28. A polynucleotide comprising a nucleotide sequence encoding the light chain of claim 19.

33. A vector comprising the polynucleotide of claim 28.

34. The vector of claim 33, wherein the vector is pEb.6G.hK with a deposit number of ATCC No. PTA-6787.

38. A host cell comprising the polynucleotide of claim 28.

22. A fragment of antibody 6G, wherein the fragment has or retains the binding specificity of antibody 6G.

23. The fragment of claim 22, wherein the fragment is a Fab, a Fab′

, a F(ab′

)₂, or a Fv.

29. A polynucleotide comprising a nucleotide sequence encoding the fragment of claim 22.

35. A vector comprising the polynucleotide of claim 29.

39. A host cell comprising the polynucleotide of claim 29.