Monoclonal Antibody

• US 20100098707A2
• Filed: 12/11/2006
• Published: 04/22/2010
• Est. Priority Date: 12/12/2005
• Status: Active Grant

• Current Assignee: AC Immune SA
• Original Assignee: AC Immune SA
• Inventors: Muhs, Andreas, Pfeifer, Andrea, Greferath, Ruth, Hickman, David, Claude, Nicolau
• Granted Patent: US 7,772,375 B2
• Time in Patent Office: Days
• US Class Current: 424/146.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: G01N 2333/4709 Amyloid plaque core protein

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

1-120. -120. (canceled)

121. A monoclonal antibody wherein:

(i) the CDR1 of the light chain variable region of the monoclonal antibody has the amino acid sequence of SEQ ID NO;

23;

(ii) the CDR2 of the light chain variable region of the monoclonal antibody has the amino acid sequence of SEQ ID NO;

24;

(iii) the CDR3 of the light chain variable region of the monoclonal antibody has the amino acid sequence of SEQ ID NO;

25;

(iv) the CDR1 of the heavy chain variable region of the monoclonal antibody has the amino acid sequence of SEQ ID NO;

26;

(v) the CDR2 of the heavy chain variable region of the monoclonal antibody has the amino acid sequence of SEQ ID NO;

27; and

(vi) the CDR3 of the heavy chain variable region of the monoclonal antibody has the amino acid sequence of SEQ ID NO;

28.

144. A pharmaceutical composition comprising a therapeutically effective amount of the monoclonal antibody according to claim 121 and a pharmaceutically acceptable carrier.

145. The pharmaceutical composition of claim 144 further comprising a biologically active agent for the treatment of diseases and disorders which are caused by or are associated with the aggregation of β

-amyloid proteins, amyloid β

fibers, amyloid β

monomers or amyloid β

oligomers.

146. The pharmaceutical composition of claim 145, wherein the biologically active agent is selected from the group consisting of compounds against oxidative stress, anti-apoptotic compounds, metal chelators, inhibitors of DNA repair, 3-amino-1-propanesulfonic acid (3APS),1,3-propanedisulfonate (1,3PDS), secretase activators, β

- and γ

- secretase inhibitors, tau proteins, neurotransmitter, β

-sheet breakers, anti-inflammatory molecules, and cholinesterase inhibitors (ChEIs).

147. The pharmaceutical composition of claim 145, wherein the biologically active agent is selected from the group consisting of tacrine, rivastigmine, donepezil, galantamine, niacin and memantine.

150. A method for preventing, treating or alleviating the effects of a disease or disorder caused by or associated with amyloid, amyloid-like proteins, or amyloid plaque formation, wherein said disease or disorder is selected from the group consisting of amyloidosis, secondary amyloidosis, age-related amyloidosis, neurological disorder, Alzheimer'"'"'s Disease, mild cognitive impairment (MC1), Lewy body dementia, Down'"'"'s syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type);

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 and macular degeneration, in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 144.

151. A method for the preparation of the pharmaceutical composition of claim 144, comprising formulating a therapeutically effective amount of the monoclonal antibody of claim 121 in a pharmaceutically acceptable form.

152. A method for reducing the plaque load in the brain of a mammal suffering from a disease or condition leading to an increased plaque load in the brain comprising administering to the animal in need of such a treatment, the pharmaceutical composition of claim 144.

153. The method of claim 152, wherein the mammal is a human.

154. The method of claim 152, wherein the plaque load in the brain is decreased by at least 20%.

155. A method for reducing the amount of plaques in the brain of a mammal suffering from a disease or condition leading to an increased plaque load in the brain, comprising administering to the mammal in need of such a treatment, the pharmaceutical composition of claim 144.

156. The method of claim 155, wherein the mammal is a human.

157. The method according of claim 155, wherein the amount of plaques in the brain is reduced by at least 10%.

158. A method for decreasing the total amount of soluble amyloid β

in the brain of a mammal suffering from a disease or condition leading to increased concentrations of soluble amyloid β

in the brain, comprising administering to the mammal in need of such a treatment, the pharmaceutical composition of claim 144.

159. The method of claim 158, wherein the mammal is a human.

160. A method for retaining or increasing cognitive memory capacity in a mammal exhibiting an amyloid-associated disease or condition comprising administering to the mammal in need of such a treatment, the pharmaceutical composition of claim 144.

161. The method of claim 160, wherein the mammal is a human.

162. A hybridoma cell line producing the monoclonal antibody of claim 121.

177. A method for monitoring minimal residual disease in a patient following treatment with the pharmaceutical composition of claim 144, wherein said method comprises:

(a) contacting the sample or a specific body part or body area containing the amyloid antigen with the pharmaceutical composition under conditions that allow the monoclonal antibody or functional fragment thereof in the pharmaceutical composition to bind to the amyloid antigen to form an immunological complex;

(b) detecting the formation of the immunological complex;

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

(d) comparing the amount of said immunological complex to a normal control value, wherein an increase in the amount of said complex compared to a normal control value indicates the presence of a minimal residual disease.

178. A method for predicting responsiveness of a patient being treated with the pharmaceutical composition of claim 144 comprising:

(a) bringing the sample or a specific body part or body area suspected to contain the amyloid antigen into contact with the pharmaceutical composition under conditions that allow the monoclonal antibody or functional fragment thereof in the pharmaceutical composition to form an immunological complex;

(b) detecting the formation of the immunological complex;

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

(d) 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 potential of being responsive to the treatment.

179. A test kit for the detection and diagnosis of amyloid-associated diseases and conditions comprising a container holding the monoclonal antibody of claim 121 and instructions for using the test kit.

189. The pharmaceutical composition of claim 146, wherein the inhibitor of DNA repair is pirenzepin or a metabolite thereof.

122-126. -126. (canceled)

128. A monoclonal antibody produced by the hybridoma cell line FP 12H3-C2, deposited as DSM ACC2750.

132-133. -133. (canceled)

134. A nucleic acid molecule comprising a nucleotide sequence encoding the light chain variable region of SEQ ID NO:

7.

135. The nucleic acid molecule of claim 134, wherein the nucleotide sequence is selected from the group consisting of SEQ ID NO:

9, a variant thereof and a complementary sequence to SEQ ID NO;

9.

138. A polynucleotide comprising a nucleotide sequence that hybridizes to the nucleic acid molecule of claim 134.

136. A nucleic acid molecule comprising a nucleotide sequence encoding the heavy chain variable region of SEQ ID NO:

8.

137. The nucleic acid molecule of claim 136, wherein the nucleotide sequence is selected from the group consisting of SEQ ID NO:

11, a variant thereof and a complementary sequence to SEQ ID NO;

11.

139. A polynucleotide comprising a nucleotide sequence that hybridizes to the nucleic acid molecule of claim 136.

140. A light chain variable region (LCVR), wherein

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

23;

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

24; and

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

25.

141. A heavy chain variable region (HCVR), wherein

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

26;

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

27; and

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

28.

142-143. -143. (canceled)

163. A hybridoma cell line producing a monoclonal antibody or functional fragment thereof having the characteristic properties of the monoclonal antibody produced by the hybridoma cell line FP 12H3, deposited as DSM ACC2752.

164. A hybridoma cell line producing a monoclonal antibody having the characteristic properties of the monoclonal antibody produced by the hybridoma cell line FP 12H3-C2, deposited as DSM ACC2750.

165. A hybridoma cell line producing a monoclonal antibody or functional fragment thereof having the characteristic properties of the monoclonal antibody produced by the hybridoma cell line FP 12H3-C2, deposited as DSM ACC2751.

166. A hybridoma cell line producing a monoclonal antibody or functional fragment thereof having the characteristic properties of the monoclonal antibody produced by the hybridoma cell line ET 7E3, deposited as DSM ACC2755.

167. A hybridoma cell line producing a monoclonal antibody or functional fragment thereof having the characteristic properties of the monoclonal antibody produced by the hybridoma cell line EJ 7H3, deposited as DSM ACC2756.

168. The hybridoma cell line FP 12H3, deposited as DSM ACC2752.

169. The hybridoma cell line FP 12H3-C2, deposited as DSM ACC2750.

170. The hybridoma cell line FP 12H3-G2, deposited as DSM ACC275 1.

171. The hybridoma cell line ET 7E3, deposited as DSM ACC2755.

172. The hybridoma cell line EJ 7H3, deposited as DSM ACC2756.

180. (canceled)

181. A nucleic acid molecule comprising a nucleotide sequence encoding the monoclonal antibody light chain or functional fragment thereof of claim 180.

182. (canceled)

183. A nucleic acid molecule comprising a nucleotide sequence encoding the monoclonal antibody heavy chain or functional fragment thereof of claim 182.

184. (canceled)

185. A monoclonal antibody, wherein the CDR1 of the light chain has the amino acid sequence of SEQ ID NO:

23;

the CDR2 of the light chain has the amino acid sequence of SEQ ID NO;

24; and

the CDR3 of the light chain has the amino acid sequence of SEQ ID NO;

25.

186. A monoclonal antibody, wherein the CDR1 of the heavy chain has the amino acid sequence of SEQ ID NO:

26;

the CDR2 of the heavy chain has the amino acid sequence of SEQ ID NO;

27; and

the CDR3 of the heavy chain has the amino acid sequence of SEQ ID NO;

28.

187. A monoclonal antibody, wherein the light chain variable region has the amino acid sequence of SEQ ID NO:

7.

188. A monoclonal antibody, wherein the heavy chain variable region has the amino acid sequence of SEQ ID NO:

8.