Humanized anti-beta-amyloid antibody

• US 7,892,544 B2
• Filed: 07/13/2007
• Issued: 02/22/2011
• Est. Priority Date: 07/14/2006
• Status: Active Grant

• Current Assignee: AC Immune SA, Genentech, Inc. (Roche Holding AG)
• Original Assignee: AC Immune SA, Genentech, Inc. (Roche Holding AG)
• Inventors: Pihlgren, Maria, Muhs, Andreas, Watts, Ryan, Pfeifer, Andrea
• Primary Examiner(s): Kolker; Daniel E
• Assistant Examiner(s): BALLARD, KIMBERLY
• Application Number:
  US11/777,777
• Publication Number:
  US 20090093002A1
• Time in Patent Office: 1,320 Days
• Field of Search: None
• US Class Current: 424/133.1
• 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: 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 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• 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: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

The present invention is related to chimeric and humanized antibody and to methods and compositions for the therapeutic and diagnostic use in the treatment of amyloidosis, a group of disorders and abnormalities associated with amyloid protein such as Alzheimer'"'"'s disease.

Claims

1. An antibody or a fragment thereof capable of specifically binding beta-amyloid peptide, peptide, said antibody or fragment thereof comprising human- or primate-derived framework regions, said antibody or fragment thereof further comprising a Heavy Chain Variable Region (HCVR) CDR1 having the amino acid sequence of SEQ ID NO:

1, an HCVR CDR2 having the amino acid sequence of SEQ ID NO;

2, and an HCVR CDR3 having the amino acid sequence of SEQ ID NO;

3.

6. The antibody or fragment thereof of claim 1 or 3 wherein the HCVR has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

15.

7. The antibody or fragment thereof of claim 1 or 3 which comprises the humanized heavy chain of SEQ ID NO:

16.

8. The antibody or fragment thereof according to claim 7, wherein the N-terminal Lys of the heavy chain constant region has been removed.

9. The antibody or fragment thereof according to any one of claims 1, 2, and 3, which antibody is of the IgG 4 isotype.

12. The antibody or fragment thereof according to claim 1 or 3, wherein the framework sequences are human germline V_H sequences of Kabat subgroup VHIII.

13. The antibody or fragment thereof of claim 1 or 3, wherein the Heavy Chain Variable Region (HCVR) has an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:

15.

14. The antibody or fragment thereof of claim 1 or 3, wherein the Heavy Chain Variable Region (HCVR) has the amino acid sequence of SEQ ID NO:

15.

16. The antibody or fragment thereof according to claim 1 or 3, wherein the Leu in position 47 in the human- or primate-derived framework region of the Heavy Chain Variable Region as shown in SEQ ID NO:

15 is replaced by an amino acid selected from the group consisting of norleucine, Ile, Val, Met, Ala, and Phe;

or the Ser in position 98 in the human- or primate-derived framework region of the Heavy Chain Variable Region as shown in SEQ ID NO;

15 is replaced by Thr.

21. The antibody or fragment thereof of claim 1, 2, or 3, which comprises the humanized light chain of SEQ ID NO:

13 and which comprises the humanized heavy chain of SEQ ID NO;

16.

22. A pharmaceutical composition comprising the antibody or fragment thereof according to any one of claims 1, 2, and 3 in an amount effective to treat one or more symptoms of an amyloidosis.

23. The pharmaceutical composition of claim 22, wherein the amyloidosis is Alzheimer'"'"'s Disease.

24. A test kit for detection and diagnosis of amyloid-associated diseases and conditions comprising the antibody or fragment thereof according to any one of claims 1, 2, and 3.

2. An antibody or a fragment thereof capable of specifically binding beta-amyloid peptide, said antibody or fragment thereof comprising human- or primate-derived framework regions, said antibody or fragment thereof further comprising a Light Chain Variable Region (LCVR) CDR1 having the amino acid sequence of SEQ ID NO:

4, an LCVR CDR2 having the amino acid sequence of SEQ ID NO;

5 or the amino acid sequence of SEQ ID NO;

5 with one amino acid substitution, and an LCVR CDR3 having the amino acid sequence of SEQ ID NO;

6.

4. The antibody or fragment thereof of claim 2 or 3 wherein the LCVR has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

12.

5. The antibody or fragment thereof according to claim 2 or 3 which comprises the humanized light chain of SEQ ID NO:

13.

11. The antibody or fragment thereof according to claim 2 or 3, wherein the framework sequences are human germline V_K sequences of Kabat subgroup VKII.

15. The antibody or fragment thereof of claim 2 or 3, wherein the Light Chain Variable Region (LCVR) has the amino acid sequence of SEQ ID NO:

12.

17. The antibody or fragment thereof according to claim 2 or 3, wherein the Tyr in position 92 in the human- or primate-derived framework region of the Light Chain Variable Region as shown in SEQ ID NO:

12 is replaced by an amino acid selected from the group consisting of Phe, Leu, Val, Ile, and Ala.

18. The antibody or fragment thereof of claim 2 or 3, wherein the CDR2 of the LCVR has the amino acid sequence of SEQ ID NO:

5, SEQ ID NO;

40, or SEQ ID NO;

41.

19. The antibody or fragment thereof of claim 2 or 3, wherein the CDR2 of the LCVR has the amino acid sequence of SEQ ID NO:

5.

20. The antibody or fragment thereof of claim 2 or 3, wherein the amino acid substitution is a conservative amino acid substitution.

3. An antibody or a fragment thereof capable of specifically binding beta-amyloid peptide, said antibody or fragment thereof comprising human- or primate-derived framework re ions said antibody or fragment thereof further comprising a Heavy Chain Variable Region (HCVR) CDR1 having the amino acid sequence of SEQ ID NO:

1, an HCVR CDR2 having the amino acid sequence of SEQ ID NO;

2, an HCVR CDR3 having the amino acid sequence of SEQ ID NO;

3, a Light Chain Variable Region (LCVR) CDR1 having the amino acid sequence of SEQ ID NO;

4, an LCVR CDR2 having the amino acid sequence of SEQ ID NO;

5 or the amino acid sequence of SEQ ID NO;

5 with one amino acid substitution, and an LCVR CDR3 having the amino acid sequence of SEQ ID NO;

6.

10. The antibody or fragment thereof of claim 3 wherein the Heavy Chain Variable Region (HCVR) has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

15 and wherein the Light Chain Variable Region (LCVR) has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO;

12.

25. An antibody or fragment thereof capable of specifically binding beta-amyloid peptide, wherein the Light Chain Variable Region (LCVR) has an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:

12 and wherein the Heavy Chain Variable Region (HCVR) has an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO;

15.

26. The antibody or fragment thereof of claim 25, wherein the HCVR has the amino acid sequence of SEQ ID NO:

15 and wherein the LCVR has the amino acid sequence of SEQ ID NO;

12.