Abeta CONFORMER SELECTIVE ANTI-Abeta GLOBULOMER MONOCLONAL ANTIBODIES

• US 20110212109A1
• Filed: 05/06/2011
• Published: 09/01/2011
• Est. Priority Date: 11/30/2006
• Status: Active Grant

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Inventors: Keller, Patrick, Striebinger, Andreas R., Ebert, Ulrich, Labkovsky, Boris, Barghorn, Stefan, Hillen, Heinz
• Granted Patent: US 8,877,190 B2
• Time in Patent Office: Days
• US Class Current: 424/172.1
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 2317/10 characterized by their source of isolation or production
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• 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 2317/565 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 2800/2821 Alzheimer
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

The subject invention relates to monoclonal antibodies that may be used in the treatment and diagnosis of Alzheimer'"'"'s Disease. In particular, the present invention relates to monoclonal antibodies referred to as 10F4 and 3C5 and to other monoclonal antibodies (e.g., murine, human or humanized) having similar properties thereto.

Claims

1. An isolated antibody having a higher affinity to Aβ

(1-42) globulomer than to at least one amyloid beta protein selected from the group consisting of Aβ

(1-42) peptide present in cerebrospinal fluid (CSF) and b) Aβ

(1-40) peptide present in CSF.

4. The isolated antibody of claim 1 or claim 2, wherein the antibody is a monoclonal antibody.

5. The isolated antibody of claim 4, wherein the antibody is a recombinant antibody.

6. The isolated antibody of claim 1 or claim 2, wherein the antibody is human or humanized.

7. The isolated antibody of claim 1 or claim 2, wherein said antibody binds to at least one epitope as a monoclonal antibody selected from the group consisting of the monoclonal antibody 10F4 obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7808 and the monoclonal antibody 3C5 obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406.

14. The isolated antibody of claim 1 or claim 2, wherein the antibody comprises at least one amino acid sequence selected from the group consisting of:

a) the amino acid sequence of the heavy chain CDR3 and the amino acid sequence of the light chain CDR3 of a monoclonal antibody (10F4) obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7808 and b) the amino acid sequence of the heavy chain CDR3 and the amino acid sequence of the light chain CDR3 of a monoclonal antibody (3C5) obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406.

15. The isolated antibody of claim 1 or claim 2, wherein the antibody comprises at least one amino acid sequence selected from the group consisting of:

a) the amino acid sequence of the heavy chain CDR2 and the amino acid sequence of the light chain CDR2 of a monoclonal antibody (10F4) obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7808 and b) the amino acid sequence of the heavy chain CDR2 and the amino acid sequence of the light chain CDR2 of a monoclonal antibody (3C5) obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406.

16. The isolated antibody of claim 1 or claim 2, wherein the antibody comprises at least one amino acid sequence selected from the group consisting of:

a) the amino acid sequence of the heavy chain CDR1 and the amino acid sequence of the light chain CDR1 of a monoclonal antibody (10F4) obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7808 and b) the amino acid sequence of the heavy chain CDR1 and the amino acid sequence of the light chain CDR1 of a monoclonal antibody (3C5) obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406.

22. An isolated nucleic acid molecule encoding the antibody of claim 1 or claim 2.

23. The isolated nucleic acid molecule of claim 22 wherein the nucleotide sequence of said molecule comprises at least one sequence selected from the group consisting of SEQ ID NO:

1, SEQ ID NO;

2, SEQ ID NO;

3 and SEQ ID NO;

4.

24. A vector comprising said isolated nucleic acid molecule of claim 23.

25. A host cell comprising said vector of claim 24.

26. A method of producing an antibody, comprising culturing said host cell of claim 25 in a culture medium for a time and under conditions suitable for production of said antibody.

27. An isolated antibody produced by said method of claim 26.

28. A composition comprising said antibody of claim 1, said antibody of claim 2 or a combination thereof.

29. The composition of claim 28, wherein the composition is a pharmaceutical composition and further comprises a pharmaceutical acceptable carrier.

33. A method for treating or preventing an amyloidosis in a patient in need of said treatment or prevention comprising administering said antibody of claim 1 or claim 2 to said patient in an amount sufficient to effect said treatment or prevention.

34. The method of claim 33 wherein said amyloidosis is Alzheimer'"'"'s disease or the amyloidosis of Down'"'"'s sydrome.

37. 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 2 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.

38. The method of claim 37 wherein said antigen is a globulomer.

39. 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 2, 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.

40. The method of claim 28 wherein said antigen is a globulomer.

41. 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 2, 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 signa generating compound, said signal indicating a diagnosis of Alzheimer'"'"'s Disease in said patient.

42. A vaccine comprising:

a) said isolated antibody of claim 1, said isolated antibody of claim 2 or a combination thereof and b) a pharmaceutically acceptable adjuvant.

43. 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 2, for a time and under conditions sufficient for said one or more compounds to bind to said isolated antibody of claim 1 or claim 2; and

b) identifying those compounds which bind to said isolated antibody of claim 1 or claim 2, said identified compounds to be used in active immunization in a patient predicated to develop Alzheimer'"'"'s Disease.

44. A kit comprising:

a) said isolated antibody of claim 1 or claim 2 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.

45. A kit comprising:

a) an anti-antibody to said isolated antibody of claim 1 or claim 2 and b) a conjugate comprising an antigen attached to a signal-generating compound.

2. An isolated antibody having a binding affinity to Aβ

(1-42) globulomer which is greater than the binding affinity to at least one amyloid beta protein selected from the group consisting of a) Aβ

(1-42) monomer, b) Aβ

(1-40) monomer, c) Aβ

(1-42) fibril and d) soluble amyloid precursor protein-alpha (sAPPα

).

3. The isolated antibody of claim 2 wherein said antibody binds with less affinity to amyloid beta protein present in non-CSF than to amyloid beta protein present in CSF.

8. An isolated antibody comprising SEQ ID NO:

5.

9. An isolated antibody comprising SEQ ID NO:

6.

10. The isolated antibody of claim 9 further comprising SEQ ID NO:

5.

11. An isolated antibody comprising SEQ ID NO:

7.

12. An isolated antibody comprising SEQ ID NO:

8.

13. The isolated antibody of claim 12 further comprising SEQ ID NO:

7.

17. An isolated antibody comprising at least one CDR selected from the group consisting of amino acid sequence:

a) SHYAWN;

b) YIDYSGSTRYLPSLKS;

c) GSGYFYGMDY;

d) HASQNINVWLS;

e) KASNLHT;

f) QQGQSYPYT;

g) NYLIE;

h) VINPGSGDTNYNENFKG;

i) GVITTGFDY;

j) RASGNIHNYLA;

k) NAKTLAD and

     1) QHFWSSPRT.

18. A hybridoma designated by American Type Culture Collection deposit number PTA-7808.

19. A monoclonal antibody (10F4) obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7808.

20. A hybridoma designated by American Type Culture Collection deposit number PTA-7406.

21. A monoclonal antibody (3C5) obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406.

30. A monoclonal antibody comprising an amino acid sequence encoded by at least one nucleotide sequence selected from the group consisting of SEQ ID NO:

1, SEQ ID NO;

2, SEQ ID NO;

3 and SEQ ID NO;

4.

31. The isolated antibody of claim 30 wherein said antibody is selected from the group consisting of a monoclonal antibody produced by a hybridoma designated by American Type Culture Collection deposit number PTA-7406 and a monoclonal antibody produced by a hybridoma designated by American Type Culture Collection deposit number PTA-7808.

32. The isolated antibody of claim 30 wherein said antibody comprises at least one amino acid sequence selected from the group consisting of SEQ ID NO:

5, SEQ ID NO;

6, SEQ ID NO;

7 and SEQ ID NO;

8.

35. An isolated antibody which binds to at least one epitope of amyloid beta protein in the brain of a patient having amyloidosis.

36. The isolated antibody of claim 35, wherein said antibody is produced by a hybridoma having an ATCC deposit number selected from the group consisting of PTA-7406 and PTA-7808.

46. The kit of claim 46 wherein said antigen is a globulomer.