Anti-amyloid beta antibodies conjugated to sialic acid-containing molecules

• US 8,323,654 B2
• Filed: 05/26/2010
• Issued: 12/04/2012
• Est. Priority Date: 05/14/2007
• Status: Active Grant

• Current Assignee: Medtronic Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Incorporated (Medtronic Plc)
• Inventors: Benz, Michael E., Shafer, Lisa L., Thakker, Deepak R.
• Primary Examiner(s): Kemmerer, Elizabeth C
• Assistant Examiner(s): BALLARD, KIMBERLY
• Application Number:
  US12/788,116
• Publication Number:
  US 20110202000A1
• Time in Patent Office: 923 Days
• Field of Search: None
• US Class Current: 424/178.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 47/6807 the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
• CPC Class Codes: A61K 47/6843 the antibody targeting a material from animals or humans
• 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 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL

Abstract

Antibody complexes including anti-Aβ antibodies conjugated with a sialic acid-containing molecule show improved bioavailability with no significant adverse effects on binding to amyloid beta.

Claims

1. An antibody complex comprising:

an isolated anti-amyloid beta antibody having (i) a variable heavy chain region including an amino acid sequence selected from the group consisting of SEQ ID NOs;

42, 44, 46, 47, 48, 49, 50 and 51, and (ii) a variable light chain region including an amino acid sequence selected from the group consisting of SEQ ID NOs;

43, 45, 52, 53 and 54; and

sialiac acid-containing molecule conjugated to the antibody.

2. An antibody complex according to claim 1, wherein the isolated antibody is a humanized antibody.

3. An antibody complex according to claim 1, wherein the variable heavy chain region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

47, SEQ ID NO;

48, SEQ ID NO;

49, SEQ ID NO;

50 and SEQ ID NO;

51.

4. An antibody complex according to claim 3, wherein the variable light chain region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

52, SEQ ID NO;

53, and SEQ ID NO;

54.

5. An antibody complex according to claim 1, wherein the variable heavy chain region comprises an amino acid sequence of SEQ ID NO:

47 and the variable light chain region comprises an amino acid sequence of SEQ ID NO;

52.

6. An antibody complex according to claim 1, wherein the variable heavy chain region comprises an amino acid sequence of SEQ ID NO:

48 and the variable light chain region comprises an amino acid sequence of SEQ ID NO;

54.

7. An antibody complex according to claim 1, wherein the variable heavy chain region comprises an amino acid sequence of SEQ ID NO:

50 and the variable light chain region comprises an amino acid sequence of SEQ ID NO;

52.

8. An antibody complex according to claim 1, wherein the variable heavy chain region comprises an amino acid sequence of SEQ ID NO:

51 and the variable light chain region comprises an amino acid sequence of SEQ ID NO;

52.

9. An antibody complex according to claim 1, wherein the variable heavy chain region comprises an amino acid sequence of SEQ ID NO:

50 and the variable light chain region comprises an amino acid sequence of SEQ ID NO;

53.

10. An antibody complex according to claim 1, wherein the variable heavy chain region comprises an amino acid sequence of SEQ ID NO:

51 and the variable light chain region comprises an amino acid sequence of SEQ ID NO;

53.

11. An antibody complex according to claim 1, wherein the isolated antibody further comprises an immunoglobulin domain.

12. An antibody complex according to claim 11, wherein the immunoglobulin domain is selected from the group consisting of IgG-1, IgG-4, and IgGM.

13. An antibody complex according to claim 1, wherein the antibody is a monoclonal antibody.

14. An antibody complex according to claim 13, wherein the antibody is a F(ab)′

₂ antibody.

15. An antibody complex according to claim 1, wherein the sialiac acid-containing molecule comprises a lipid head-group and a sialic acid group.

16. An antibody complex according to claim 15, wherein the lipid head-group is a phospholipid.

17. An antibody complex according to claim 1, wherein the sialic acid-containing molecule is selected from the group consisting of capsular polysialic acid, sialic acid-containing gangliosides, and colominic acid.

18. An antibody complex according to claim 1, wherein the sialic acid-containing molecule is a capsular polysialic acid.

19. A composition comprising an antibody complex according to claim 1.

20. A composition according to claim 19, further comprising a pharmaceutically acceptable diluent.

21. A composition according to claim 19, wherein the antibody is present in the composition in an amount effective to treat a disease associated with increased or aberrant soluble Aβ

, Aβ

fibrils or Aβ

plaques when administered to a subject in need thereof.

22. A system comprising an implantable infusion device and a composition according to claim 19, wherein the composition is an injectable composition, wherein the infusion device comprises a reservoir for housing the composition, and wherein the composition is housed in the reservoir.

23. A method for treating a disease associated with increased or aberrant soluble Aβ

, Aβ

fibrils or Aβ

plaques in a subject in need thereof, comprising;

administering an effective amount of the antibody of claim 1 to the subject.

24. A method according to claim 23, wherein the subject is suffering from or at risk of Alzheimer'"'"'s disease.

25. A method according to claim 23, wherein the subject is suffering from or at risk of Lewy body dementia.

26. A method according to claim 23, wherein the subject is suffering from or at risk of Down'"'"'s Syndrome.

27. A method according to claim 23, wherein the subject is suffering from or at risk of cerebral amyloid angiopathy.

28. A method according claim 23, wherein administering the antibody to the subject comprises administering the antibody directly to the subject'"'"'s central nervous system.

29. A method according to claim 28, wherein administering the antibody directly to the subject'"'"'s central nervous system comprises administering the antibody directly to cerebrospinal fluid of the subject.

30. A method according to claim 23, wherein the antibody is administered via an infusion device implanted in the subject.