MONOCLONAL ANTIBODIES AND USES THEREOF

• US 20090238831A1
• Filed: 11/30/2006
• Published: 09/24/2009
• Est. Priority Date: 11/30/2005
• Status: Active Grant

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Inventors: Hillen, Hinz, Keller, Patrick, Labkovsky, Boris, Barghorn, Stefan, Striebinger, Andreas R., Ebert, Ulrich
• Granted Patent: US 8,497,072 B2
• Time in Patent Office: Days
• US Class Current: 424/139.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• 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 37/04 Immunostimulants
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/20 characterized by taxonomic origin
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 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
• CPC Class Codes: G01N 2333/4709 Amyloid plaque core protein
• CPC Class Codes: G01N 2500/20 cell-free systems
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 33/577 involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens; G01N33/53 - G01N33/576 take precedence
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

The subject invention relates to monoclonal antibodies (e.g., 8F5 and 8C5) that may be used, for example, in the prevention, treatment and diagnosis of Alzheimer'"'"'s Disease or other neurodegenerative disorders.

Claims

1. An isolated antibody that binds with greater specificity to an amyloid beta (Aβ

) protein globulomer than to an amyloid beta protein monomer.

2. The isolated antibody of claim 1 wherein said antibody is monoclonal.

3. The isolated antibody of claim 2 wherein the ratio of binding specificity to said globulomer and said monomer is at least 1.4.

4. The isolated antibody of claim 3 wherein said ratio is 1.4 to 16.9.

5. The isolated antibody of claim 4 wherein said amyloid beta protein monomer is selected from the group consisting of Aβ

(1-42) monomer and Aβ

(1-40) monomer.

6. The isolated antibody of claim 5 wherein said monoclonal antibody is produced by a hybridoma having American Type Culture Collection designation number PTA-7238 or PTA-7407.

42. A method of treating or preventing Alzheimer'"'"'s Disease in a patient in need of said treatment or prevention comprising administering said isolated antibody of claim 1 or claim 6 to said patient in an amount sufficient to effect said treatment or prevention.

43. The method of claim 42 wherein said isolated antibody is administered via a route selected from the group consisting of intramuscular administration, intravenous administration and subcutaneous administration.

44. A method of diagnosing Alzheimer'"'"'s Disease in a patient suspected of having this disease comprising the steps of:

a. isolating a biological sample from said patient;

b. contacting said biological sample with said isolated antibody of claim 1 or claim 6 for a time and under conditions sufficient for formation of antigen/antibody complexes; and

c. detecting presence of said antigen/antibody complexes in said sample, presence of said complexes indicating a diagnosis of Alzheimer'"'"'s Disease in said patient.

45. The method of claim 44 wherein said antigen is a globulomer.

46. A method of diagnosing Alzheimer'"'"'s Disease in a patient suspected of having this disease comprising the steps of:

a. isolating a biological sample from said patient;

b. contacting said biological sample with an antigen for a time and under conditions sufficient for the formation of antibody/antigen complexes;

c. adding a conjugate to the resulting antibody/antigen complexes for a time and under conditions sufficient to allow said conjugate to bind to the bound antibody, wherein said conjugate comprises said isolated antibody of claim 1 or claim 6, attached to a signal generating compound capable of generating a detectable signal; and

d. detecting the presence of an antibody which may be present in said biological sample, by detecting a signal generated by said signal generating compound, said signal indicating a diagnosis of Alzheimer'"'"'s Disease in said patient.

47. The method of claim 46 wherein said antigen is a globulomer.

48. A method of diagnosing Alzheimer'"'"'s Disease in a patient suspected of having Alzheimer'"'"'s Disease comprising the steps of:

a. isolating a biological sample from said patient;

b. contacting said biological sample with anti-antibody, wherein said anti-antibody is specific for said antibody of claim 1 or claim 6, for a time and under conditions sufficient to allow for formation of anti-antibody/antibody complexes, said complexes containing antibody present in said biological sample;

c. adding a conjugate to resulting anti-antibody/antibody complexes for a time and under conditions sufficient to allow said conjugate to bind to bound antibody, wherein said conjugate comprises an antigen, which binds to a signal generating compound capable of generating a detectable signal; and

d. detecting a signal generated by said signal generating compound, said signal indicating a diagnosis of Alzheimer'"'"'s Disease in said patient.

49. A composition comprising said isolated antibody of claim 1 or claim 6.

50. A method of preventing or treating Alzheimer'"'"'s Disease in a patient in need of said prevention or treatment comprising the step of administering said composition of claim 49 to said patient in an amount sufficient to effect said prevention or treatment.

51. A vaccine comprising said isolated antibody of claim 1 or claim 6 and a pharmaceutically acceptable adjuvant.

52. A method of preventing or treating Alzheimer'"'"'s Disease in a patient in need of said prevention or treatment comprising the step of administering said vaccine of claim 51 to said patient in an amount sufficient to effect said prevention or treatment.

53. A method of identifying compounds suitable for active immunization of a patient predicted to develop Alzheimer'"'"'s Disease comprising the steps of:

a) exposing one or more compounds of interest to said isolated antibody of claim 1 or claim 6 for a time and under conditions sufficient for said one or more compounds to bind to said isolated antibody of claim 1 or claim 6; and

b) identifying those compounds which bind to said isolated antibody of claim 1 or claim 6, said identified compounds to be used in active immunization in a patient predicated to develop Alzheimer'"'"'s Disease.

54. A kit comprising:

a) said isolated antibody of claim 1 or claim 6 and b) a conjugate comprising an antibody attached to a signal-generating compound, wherein said antibody of said conjugate is different from said isolated antibody.

55. A kit comprising:

a) an anti-antibody to said isolated antibody of claim 1 or claim 6 and b) a conjugate comprising an antigen attached to a signal-generating compound.

56. The kit of claim 55 wherein said antigen is a globulomer.

7. A hybridoma having American Type Culture Collection designation number PTA-7238.

8. A monoclonal antibody (8F5) produced by said hybridoma of claim 7.

9. A monoclonal antibody comprising a variable heavy chain encoded by SEQ ID NO:

1.

10. The monoclonal antibody of claim 9 wherein said antibody is human or humanized.

11. A monoclonal antibody comprising a variable light chain encoded by SEQ ID NO:

2.

12. The monoclonal antibody of claim 11 wherein said antibody is human or humanized.

13. The monoclonal antibody of claim 11 further comprising a variable light heavy chain encoded by SEQ ID NO:

1.

14. The monoclonal antibody of claim 13 wherein said antibody is human or humanized.

15. A monoclonal antibody comprising SEQ ID NO:

3.

16. The monoclonal antibody of claim 15 wherein said antibody is human or humanized.

17. A monoclonal antibody comprising SEQ ID NO:

4.

18. The monoclonal antibody of claim 17 wherein said antibody is human or humanized.

19. The monoclonal antibody of claim 17 further comprising SEQ ID NO:

3.

20. The monoclonal antibody of claim 19 wherein said antibody is human or humanized.

21. An isolated antibody that binds with greater specificity to an amyloid beta protein globulomer than to an amyloid beta protein fibril.

22. The isolated antibody of claim 22 wherein said antibody is monoclonal.

23. The isolated antibody of claim 23 wherein said monoclonal antibody is produced by a hybridoma having American Type Culture Collection designation number PTA-7238 or PTA-7407.

24. A hybridoma having American Type Culture Collection designation number PTA-7407.

25. A monoclonal antibody (8C5) produced by said hybridoma of claim 24.

26. A monoclonal antibody comprising a variable heavy chain encoded by SEQ ID NO:

11.

27. The monoclonal antibody of claim 26 wherein said antibody is human or humanized.

28. A monoclonal antibody comprising a variable light chain encoded by SEQ ID NO:

12.

29. The monoclonal antibody of claim 28 wherein said antibody is human or humanized.

30. The monoclonal antibody of claim 28 further comprising a variable light chain encoded by SEQ ID NO:

11.

31. The monoclonal antibody of claim 30 wherein said antibody is human or humanized.

32. A monoclonal antibody comprising SEQ ID NO:

19.

33. The monoclonal antibody of claim 32 wherein said antibody is human or humanized.

34. A monoclonal antibody comprising SEQ ID NO:

20.

35. The monoclonal antibody of claim 34 wherein said antibody is human or humanized.

36. A monoclonal antibody comprising a variable heavy chain, wherein said variable heavy chain comprises at least one complementarity determining region (CDR) selected from the group consisting of SEQ ID NO:

13, SEQ ID NO;

14 and SEQ ID NO;

15.

37. A monoclonal antibody comprising a variable light chain, wherein said variable light chain comprises at least one CDR selected from the group consisting of SEQ ID NO:

16, SEQ ID NO;

17 and SEQ ID NO;

18.

38. The monoclonal antibody of claim 37 further comprising a variable heavy chain, wherein said variable heavy chain comprises at least one CDR selected from the group consisting of SEQ ID NO:

13, SEQ ID NO;

14 and SEQ ID NO;

15.

39. A monoclonal antibody comprising a variable heavy chain, wherein said variable heavy chain comprises at least one complementarity determining region (CDR) selected from the group consisting of SEQ ID NO:

5, SEQ ID NO;

6 and SEQ ID NO;

7.

40. A monoclonal antibody comprising a variable light chain, wherein said variable light chain comprises at least one CDR selected from the group consisting of SEQ ID NO:

6, SEQ ID NO;

9 and SEQ ID NO;

10.

41. The monoclonal antibody of claim 40 further comprising a variable heavy chain, wherein said variable heavy chain comprises at least one CDR selected from the group consisting of SEQ ID NO:

5, SEQ ID NO;

6 and SEQ ID NO;

7.