ANTIBODIES

• US 20100150906A1
• Filed: 10/02/2007
• Published: 06/17/2010
• Est. Priority Date: 07/14/2006
• Status: Active Grant

• Current Assignee: AC Immune SA, Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Pihlgren, Maria, Pfeifer, Andrea, Muhs, Andreas, Watts, Ryan
• Granted Patent: US 8,124,353 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• 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 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• 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 j3-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

1-170. -170. (canceled)

171. A pharmaceutical composition comprising a chimeric antibody or a fragment thereof, or a humanized antibody or a fragment thereof, which antibody recognizes and binds to at least one distinct binding site on the β

-amyloid protein wherein said distinct binding site comprises at least one or at least two consecutive amino acid residues predominantly involved in the binding of the antibody, selected from the group consisting of;

(i) -Lys-Leu- within SEQ ID NO;

10;

(ii) -Phe-Phe- within SEQ ID NO;

9;

(iii) His within the following sequence;

174. The pharmaceutical composition of claim 171 in combination with physical methods, lipid-based methods, and receptor and channel-based methods for transporting the antibodies across the blood-brain barrier, for use in the treatment or alleviation of the effects of amyloidosis, a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis such as diseases including, but not limited to, neurological disorders such as Alzheimer'"'"'s Disease (AD and diseases or conditions characterized by a loss of cognitive memory capacity such as, for example, mild cognitive impairment (MCI). Lewy body dementia, Down'"'"'s syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type);

the Guam Parkinson-Dementia complex;

as well as other diseases which are based on or associated with amyloid-like proteins such as 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, and others, including macular degeneration.

175. A method for monitoring minimal residual disease in a patient following treatment with a pharmaceutical composition according to claim 171, 172, or 173, wherein said method comprises:

a. bringing a sample suspected to contain the amyloid antigen into contact with an antibody as described in claim 171, 172, or 173, which antibody binds an epitope of the amyloid protein;

b. allowing the antibody to bind to the amyloid antigen 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 antigen in the sample,

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.

176. A method for predicting responsiveness of a patient being treated with a pharmaceutical composition according to claim 171, 172, or 173, comprising

a. bringing a sample suspected to contain the amyloid antigen into contact with an antibody as described in claim 171, 172, or 173, which antibody binds an epitope of the amyloid protein;

b. allowing the antibody to bind to the amyloid antigen 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 antigen in the sample,

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.

177. A method for reducing the plaque load in the brain of an animal, particularly a mammal, but especially a human suffering from a disease or condition leading to an increased plaque load in the brain comprising administering to an animal, particularly a mammal, more particularly a human in need of such a treatment, a therapeutically effective amount of the pharmaceutical composition of claim 171, 172, 173, or 174.

178. A method for reducing the amount of plaques in the brain of an animal, particularly a mammal, but especially a human suffering from a disease or condition leading to an increased plaque load in the brain comprising administering to an animal, particularly mammal, more particularly a human in need of such a treatment, a therapeutically effective amount of the pharmaceutical composition of claim 171, 172, 173, or 174.

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

in the brain of an animal, particularly a mammal, but especially a human suffering from a disease or condition leading to increased concentrations of soluble Aβ

in the brain comprising administering to an animal, particularly a mammal, more particularly a human in need of such a treatment, a therapeutically effective amount of the pharmaceutical composition of claim 171, 172, 173, or 174.

180. A method for retaining or increasing cognitive memory capacity in a mammal exhibiting an amyloid-associated disease or condition comprising administering to an animal, particularly a mammal, more particularly a human in need of such a treatment, a therapeutically effective amount of the pharmaceutical composition of claim 171, 172, 173, or 174.

172. A pharmaceutical composition comprising a humanized antibody or a fragment thereof comprising variable regions with human- or primate-derived framework regions and CDRs with an amino acid sequence of SEQ ID NO:

1 representing CDR1, SEQ ID NO;

2 representing CDR2 and SEQ ID NO;

3 representing CDR3 of the Heavy Chain Variable Region (HCVR) and SEQ ID NO;

4 representing CDR1, SEQ ID NO;

5 representing CDR2 and SEQ ID NO;

6 representing CDR3 of the Light Chain Variable Region (LCVR).

173. The pharmaceutical composition of claim 172, wherein the chimeric antibody or fragment thereof, or humanized antibody or fragment thereof comprises the humanized light chain of SEQ ID NO:

13, and the humanized heavy chain of SEQ ID NO;

16.