Monoclonal antibody

• US 9,175,094 B2
• Filed: 11/12/2013
• Issued: 11/03/2015
• 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): BALLARD, KIMBERLY
• Application Number:
  US14/077,915
• Publication Number:
  US 20140199323A1
• Time in Patent Office: 721 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids
• 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 2317/76 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 2800/50 Determining the risk of developing a disease
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• 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 method for treating a disease or disorder which is caused by or associated with amyloid or amyloid-like proteins, comprising administering to a subject in need thereof:

(a) a monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FG1F9E4, deposited on May 25, 2007 and given deposit number DSM ACC2845;

(b) a monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FK2A6A6, deposited on May 25, 2007 and given deposit number DSM ACC2846;

or

(c) an anti-amyloid beta antibody, or active fragment thereof, wherein

i. complementarity determining region (CDR) 1 of the light chain variable region has the amino acid sequence of SEQ ID NO;

11;

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

12;

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

13;

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

14;

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

15; and

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

16.

2. The method of claim 1, which comprises administering to the subject the monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FG1F9E4, deposited on May 25, 2007 and given deposit number DSM ACC2845.

3. The method of claim 1, which comprises administering to the subject the monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FK2A6A6, deposited on May 25, 2007 and given deposit number DSM ACC2846.

4. The method of claim 1, which comprises administering to the subject the 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:

11;

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

12;

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

13;

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

14;

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

15; and

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

16.

5. The method of claim 1, further comprising administering to the subject a 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.

6. The method of claim 5, wherein the inhibitor of DNA repair is pirenzepin or a metabolite thereof.

7. The method of claim 5, wherein the cholinesterase inhibitor is tacrine, rivastigmine, donepezil, galantamine or a nutritive supplement.

8. The method of claim 1, wherein the subject is human.

9. A method of treating or alleviating the effects of a disease or disorder caused by or associated with amyloid or amyloid-like proteins comprising administering to a subject in need thereof:

(a) a monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FG1F9E4, deposited on May 25, 2007 and given deposit number DSM ACC2845;

(b) a monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FK2A6A6, deposited on May 25, 2007 and given deposit number DSM ACC2846;

or

(c)

an 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;

11;

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

12;

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

13;

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

14;

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

15; and

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

16,

such that the effects of the disease or disorder are treated or alleviated.

10. The method of claim 9, wherein the disease or disorder is amyloidosis, a neurological disorder, Guam Parkinson-Dementia complex, progressive supranuclear palsy, multiple sclerosis, Creutzfeld Jacob disease, Parkinson'"'"'s disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), inclusion-body myositis (IBM), Adult Onset Diabetes;

senile cardiac amyloidosis;

endocrine tumors, or macular degeneration.

11. The method of claim 10, wherein the neurological disorder is Alzheimer'"'"'s Disease.

12. The method of claim 9, wherein the disease or disorder is a condition characterized by a loss of cognitive memory capacity.

13. The method of claim 12, wherein the condition characterized by a loss of cognitive memory capacity is mild cognitive impairment (MCI), Lewy body dementia, Down'"'"'s syndrome, or hereditary cerebral hemorrhage with amyloidosis (Dutch type).

14. The method of claim 9, which comprises administering to the subject the monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FG1F9E4, deposited on May 25, 2007 and given deposit number DSM ACC2845.

15. The method of claim 9, which comprises administering to the subject the monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FK2A6A6, deposited on May 25, 2007 and given deposit number DSM ACC2846.

16. The method of claim 9, which comprises administering to the subject the 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:

11;

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

12;

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

13;

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

14;

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

15; and

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

16.

17. The method of claim 9, further comprising administering to the subject a 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.

18. The method of claim 17, wherein the inhibitor of DNA repair is pirenzepin or a metabolite thereof.

19. The method of claim 17, wherein the cholinesterase inhibitor is tacrine, rivastigmine, donepezil, galantamine or a nutritive supplement.

20. The method of claim 9, wherein the subject is human.

21. A method for reducing the plaque load in the brain of a subject suffering from a disease or condition associated with an increased plaque load in the brain comprising administering to the subject a therapeutically effective amount of:

(a) a monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FG1F9E4, deposited on May 25, 2007 and given deposit number DSM ACC2845;

(b) a monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FK2A6A6, deposited on May 25, 2007 and given deposit number DSM ACC2846;

or

(c)

an 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;

11;

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

12;

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

13;

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

14;

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

15; and

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

16.

22. The method of claim 21, which comprises administering to the subject the monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FG1F9E4, deposited on May 25, 2007 and given deposit number DSM ACC2845.

23. The method of claim 21, which comprises administering to the subject the monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FK2A6A6, deposited on May 25, 2007 and given deposit number DSM ACC2846.

24. The method of claim 21, which comprises administering to the subject the 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:

11;

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

12;

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

13;

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

14;

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

15; and

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

16.

25. The method of claim 21, further comprising administering to the subject a 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.

26. The method of claim 25, wherein the inhibitor of DNA repair is pirenzepin or a metabolite thereof.

27. The method of claim 25, wherein the cholinesterase inhibitor is tacrine, rivastigmine, donepezil, galantamine or a nutritive supplement.

28. The method of claim 21, wherein the subject is human.

29. 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 concentrations of soluble Aβ

in the brain comprising administering to the subject a therapeutically effective amount of;

(a) a monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FG1F9E4, deposited on May 25, 2007 and given deposit number DSM ACC2845;

(b) a monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FK2A6A6, deposited on May 25, 2007 and given deposit number DSM ACC2846;

or

(c)

an 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;

11;

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

12;

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

13;

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

14;

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

15; and

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

16.

30. The method of claim 29, which comprises administering to the subject the monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FG1F9E4, deposited on May 25, 2007 and given deposit number DSM ACC2845.

31. The method of claim 29, which comprises administering to the subject the monoclonal antibody, or an active fragment thereof, which is produced by hybridoma cell line FK2A6A6, deposited on May 25, 2007 and given deposit number DSM ACC2846.

32. The method of claim 29, which comprises administering to the subject the 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:

11;

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

12;

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

13;

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

14;

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

15; and

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

16.

33. The method of claim 29, further comprising administering to the subject a 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.

34. The method of claim 33, wherein the inhibitor of DNA repair is pirenzepin or a metabolite thereof.

35. The method of claim 33, wherein the cholinesterase inhibitor is tacrine, rivastigmine, donepezil, galantamine or a nutritive supplement.

36. The method of claim 29, wherein the subject is human.