Monoclonal antibody

• US 8,048,420 B2
• Filed: 06/12/2008
• Issued: 11/01/2011
• Est. Priority Date: 06/12/2007
• Status: Active Grant

• Current Assignee: AC Immune SA, Genentech, Inc. (Roche Holding AG)
• Original Assignee: AC Immune SA, Genentech, Inc. (Roche Holding AG)
• Inventors: Pfeifer, Andrea, Pihlgren, Maria, Muhs, Andreas, Watts, Ryan
• Primary Examiner(s): Kolker; Daniel E
• Application Number:
  US12/213,007
• Publication Number:
  US 20090017041A1
• Time in Patent Office: 1,237 Days
• Field of Search: None
• US Class Current: 424/141.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/0007 Nervous system antigens; Prions
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/6911 the form being a liposome
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: G01N 2333/4709 Amyloid plaque core protein
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

The present invention is related to methods and compositions for the therapeutic and diagnostic use in the treatment of diseases and disorders which are caused by or associated with amyloid or amyloid-like proteins including amyloidosis, a group of disorders and abnormalities associated with amyloid protein such as Alzheimer'"'"'s disease. The present invention provides novel methods and compositions comprising highly specific and highly effective antibodies having the ability to specifically recognize and bind to specific epitopes from a range of β-amyloid proteins. The antibodies enabled by the teaching of the present invention are particularly useful for the treatment of diseases and disorders which are caused by or associated with amyloid or amyloid-like proteins including amyloidosis, a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis including, but not limited to, neurological disorders such as Alzheimer'"'"'s Disease (AD).

Claims

1. A monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line EJ1A9, deposited on May 25, 2007 and given deposit number DSM ACC2844.

6. A therapeutic composition comprising the antibody or active fragment thereof according to claim 1, 2, 3, 4, or 5 in a therapeutically effective amount, and optionally further comprising a pharmaceutically acceptable carrier, a diluent, and/or an excipient.

7. The composition of claim 6, further comprising a further biologically active substance selected from the group consisting of an anti-apoptotic compound, a metal chelator, an inhibitor of DNA repair, 3-amino-1-propanesulfonic acid (3APS), 1,3-propanedisulfonate (1,3PDS), a secretase activator, a β

-secretase inhibitor, a γ

-secretase inhibitor, a tau protein, a neurotransmitter, a β

-sheet breaker, an anti-inflammatory molecule, and a cholinesterase inhibitor.

8. The composition of claim 7, wherein the inhibitor of DNA repair is pirenzepin or a metabolite thereof.

9. The composition of claim 7, wherein the cholinesterase inhibitor is tacrine, rivastigmine, donepezil, galantamine, or a nutritive supplement.

10. The therapeutic composition of claim 7 comprising one or more of a pharmaceutically acceptable carrier, a diluent or an excipient.

11. A test kit comprising the antibody or active fragment thereof, of claim 1, 2, 3, 4, or 5 and optionally further comprising instructions for using the antibodies for the purpose of binding to amyloid protein to form an immunological complex and detecting the formation of the immunological complex such that presence or absence of the immunological complex correlates with presence or absence of amyloid protein.

12. A cell line characterized in that it produces the antibody, or active fragment thereof, of claim 1, 2, 3, 4, or 5.

13. A method for treating a disease or condition associated with increased concentration of Aβ

in the brain of a subject in need thereof, comprising administering the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5 to the subject.

14. A method according to claim 13, wherein the disease or condition is selected from the group consisting of Alzheimer'"'"'s disease, mild cognitive impairment, Down'"'"'s syndrome, and hereditary cerebral hemorrhage with amyloidosis (Dutch type).

15. A method of treating or alleviating the effects of a disease or condition associated with increased concentration of Aβ

in the brain of a subject in need thereof, comprising administering the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5 to the subject such that the effects of the disease or condition are treated and/or alleviated.

16. A method of treating or alleviating the effects of a disease or condition associated with increased concentration of Aβ

in the brain of a subject in need thereof, comprising administering the composition of claim 6 to the subject.

17. A method for reducing the plaque load in the brain of a subject suffering from a disease or condition associated with increased concentration of Aβ

in the brain comprising administering to the subject a therapeutically effective amount of the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5.

18. A method according to claim 17, wherein the disease or condition is Alzheimer'"'"'s disease, mild cognitive impairment, Down'"'"'s syndrome, or hereditary cerebral hemorrhage with amyloidosis (Dutch type).

19. A method for reducing the amount of plaques in the brain of a subject suffering from a disease or condition associated with increased concentration of Aβ

in the brain comprising administering to the subject a therapeutically effective amount of the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5.

20. A method according to claim 19, wherein the disease or condition is Alzheimer'"'"'s disease, mild cognitive impairment, Down'"'"'s syndrome, or hereditary cerebral hemorrhage with amyloidosis (Dutch type).

21. A method for decreasing the total amount of soluble Aβ

in the brain of a subject suffering from a disease or condition associated with increased concentration of Aβ

in the brain comprising administering to the subject a therapeutically effective amount of the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5.

22. A method according to claim 21, wherein the disease or condition is Alzheimer'"'"'s disease, mild cognitive impairment, Down'"'"'s syndrome, or hereditary cerebral hemorrhage with amyloidosis (Dutch type).

23. A method for retaining or increasing cognitive memory capacity in a subject suffering from a disease or condition associated with increased concentration of Aβ

in the brain comprising administering to the subject a therapeutically effective amount of the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5.

24. A method according to claim 23, wherein the disease or condition is Alzheimer'"'"'s disease, mild cognitive impairment, Down'"'"'s syndrome, or hereditary cerebral hemorrhage with amyloidosis (Dutch type).

25. A method of treating or alleviating the effects of Alzheimer'"'"'s disease in a subject in need thereof comprising administering the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5 to the subject.

26. A method of treating or alleviating the effects of Alzheimer'"'"'s disease in a subject in need thereof comprising administering the composition of claim 6 to the subject.

27. A method of treating or alleviating the effects of mild cognitive impairment in a subject in need thereof comprising administering the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5 to the subject.

28. A method of treating or alleviating the effects of mild cognitive impairment in a subject in need thereof comprising administering the composition of claim 6 to the subject.

29. A method of treating or alleviating the effects of Down'"'"'s syndrome in a subject in need thereof comprising administering the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5 to the subject.

30. A method of treating or alleviating the effects of Down'"'"'s syndrome in a subject in need thereof comprising administering the composition of claim 6 to the subject.

31. A method of treating or alleviating the effects of hereditary cerebral hemorrhage with amyloidosis (Dutch type) in a subject in need thereof comprising administering the antibody or active fragment thereof of claim 1, 2, 3, 4, or 5 to the subject.

32. A method of treating or alleviating the effects of hereditary cerebral hemorrhage with amyloidosis (Dutch type) in a subject in need thereof comprising administering the composition of claim 6 to the subject.

33. A method of diagnosis of or of diagnosing a predisposition to a disease or condition associated with increased concentration of Aβ

in the brain in a patient comprising detecting the immunospecific binding of a antibody or an active fragment thereof to an epitope of the amyloid protein in a sample or in situ which includes the steps of

(a) bringing the sample or a specific body part or body area suspected to contain the amyloid protein into contact with the antibody or active fragment thereof according to claim 1, 2, 3, 4, or 5, which antibody binds an conformational epitope of the amyloid protein;

(b) allowing the antibody to bind to dc amyloid protein to form an immunological complex;

(c) detecting the formation of the immunological complex; and

(d) correlating the presence or absence of the immunological complex with the presence or absence of amyloid protein in the sample or specific body part or area.

34. A method of determining the extent of amyloidogenic plaque burden in a tissue comprising

(a) obtaining a sample representative of the tissue under investigation;

(b) testing said sample for the presence of amyloid protein with the antibody or active fragment thereof according to claim 1, 2, 3, 4, or 5;

(c) determining the amount of antibody bound to the antigen; and

(d) calculating the plaque burden in the tissue.

35. A method for monitoring minimal residual disease in a patient suffering from a disease or condition associated with increased concentration of Aβ

in the brain following treatment with at least one antibody or active fragment thereof according to claim 1, 2, 3, 4, or 5, wherein said method comprises;

(a) bringing the sample or a specific body part or body area suspected to contain the amyloid protein into contact with the antibody or active fragment thereof according to claim 1, 2, 3, 4, or 5, which antibody binds an conformational epitope of the amyloid protein;

(b) allowing the antibody to bind to the amyloid protein to form an immunological complex;

(c) detecting the formation of the immunological complex;

(d) correlating the presence or absence of the immunological complex with the presence or absence of amyloid protein in the sample or specific body part or area; and

(e) comparing the amount of said immunological complex to a normal control value,

wherein an increase in the amount of said aggregate compared to a normal control value indicates that said patient still suffers from a minimal residual disease.

36. A method for predicting responsiveness of a patient suffering from a disease or condition associated with increased concentration of Aβ

in the brain being treated with at least one antibody or active fragment thereof according to claim 1, 2, 3, 4, or 5, comprising

(a) bringing the sample or a specific body part or body area suspected to contain the amyloid protein into contact with the antibody or active fragment thereof according to claim 1, 2, 3, 4, or 5, which antibody binds an conformational epitope of the amyloid protein;

(b) allowing the antibody to bind to the amyloid protein to form an immunological complex;

(c) detecting the formation of the immunological complex;

(d) correlating the presence or absence of the immunological complex with the presence or absence of amyloid protein in the sample or specific body part or area; and

(e) comparing the amount of said immunological complex before and after onset of the treatment,

wherein a decrease in the amount of said aggregate indicates that said patient has a high potential of being responsive to the treatment.

2. A monoclonal antibody, or an active fragment thereof, which is (a) capable of specifically binding beta-amyloid peptide, and (b) comprises the amino acid sequences of SEQ ID NOs:

7-8.

3. An isolated anti-amyloid beta antibody, or active fragment thereof, wherein

i. CDR1 of the light chain variable region has the amino acid sequence of SEQ ID NO:

9;

ii. CDR2 of the light chain variable region has the amino acid sequence of SEQ ID NO;

10; and

iii. CDR3 of the light chain variable region has the amino acid sequence of SEQ ID NO;

11.

4. An isolated anti-amyloid beta antibody, or active fragment thereof, wherein

i. CDR1 of the heavy chain variable region has the amino acid sequence of SEQ ID NO:

12;

ii. CDR2 of the heavy chain variable region has the amino acid sequence of SEQ ID NO;

13; and

iii. CDR3 of the heavy chain variable region has the amino acid sequence of SEQ ID NO;

14.

5. An isolated anti-amyloid beta antibody, or active fragment thereof, wherein

i. CDR1 of the light chain variable region has the amino acid sequence of SEQ ID NO:

9;

ii. CDR2 of the light chain variable region has the amino acid sequence of SEQ ID NO;

10;

iii. CDR3 of the light chain variable region has the amino acid sequence of SEQ ID NO;

11;

iv. CDR1 of the heavy chain variable region has the amino acid sequence of SEQ ID NO;

12;

v. CDR2 of the heavy chain variable region has the amino acid sequence of SEQ ID NO;

13; and

vi. CDR3 of the heavy chain variable region has the amino acid sequence of SEQ ID NO;

14.