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Methods of treatment for alzheimer's disease and huntington's disease

a technology for alzheimer's disease and huntingtons disease, applied in immunological disorders, metabolism disorders, antibody medical ingredients, etc., can solve the problems of gradual degeneration of patients, reduced neuron number, and reduced clinical effectiveness of existing drugs, and achieve only modest symptomatic reli

Inactive Publication Date: 2016-06-09
ANNEXON +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent provides anti-C1q antibodies and methods for using them to treat or prevent Alzheimer's disease and Huntington's disease. These antibodies can inhibit the classical pathway of complement activation by neutralizing complement factor C1q, which is involved in the development of these diseases. The patent also provides methods for administering the anti-C1q antibodies to patients and using them in the manufacture of a medicament for treating or preventing these diseases. The technical effect of the patent is to provide a novel approach for treating and preventing these neurological disorders by targeting a specific molecule in the body that is associated with their development.

Problems solved by technology

These cognitive disorders are caused by an increase in cell death processes that results in a great reduction of neuron number, behavioral changes and a general, gradual degeneration that leads to the patient's death.
There is currently no disease modifying therapy for Alzheimer's disease and existing drugs only provide modest symptomatic relief.
However, one problem is that, to date, antibodies designed to facilitate clearance of plaques and drugs designed to preserve mitochondrial function have failed to meet primary endpoints of mid-stage clinical trials (Delrieu et al., 2012).
These disappointing results have stimulated a reevaluation of the mechanisms underlying the disease, particularly the role of plaques.

Method used

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  • Methods of treatment for alzheimer's disease and huntington's disease
  • Methods of treatment for alzheimer's disease and huntington's disease
  • Methods of treatment for alzheimer's disease and huntington's disease

Examples

Experimental program
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Effect test

example 1

Production of Anti-C1q Antibodies

[0262]The anti-C1q antibody M1 was generated by Antibody Solutions Inc. (Sunnyvale Calif.) by immunizing C1q knockout mice with human C1q using standard mouse immunization and hybridoma screening technologies (Milstein, C (1999). Bioessays 21: 966-73; Mark Page, Robin Thorpe, The Protein Protocols Handbook 2002, Editors: John M. Walker. pp 1111-1113).

[0263]The anti-C1q antibodies 1C7, 2A1, 3A2, and 5A3 were generated at ImmunoPrecise Ltd (Victoria, BC Canada) by immunizing mice with human C1q protein purified from human plasma (Complement Technology Inc. Tyler Tex., Cat #A-099). In brief, female BALB / c mice were injected intraperitoneal with 25 μg of protein in complete Freund's adjuvant (CFA) on Day 0 and boosts were done with 25 μg of C1q enzyme in incomplete Freund's adjuvant (IFA) on days 21, 42, 52, and a final intravenous boost on Day 63. Four days following the final boost the mice were euthanized, spleens removed and splenocytes were fused wi...

example 2

Anti-C1q Antibodies Specifically Bind to C1q

ELISA Screening

[0265]Anti-C1q antibodies 1C7, 2A1, 3A2, and 5A3 were screened for C1q-binding using standard ELISA protocols.

[0266]Briefly, the day before the assay was performed, 96-well microtiter plates were coated at 0.2 μg / well of C1q-enzyme antigen in 100 μL / well carbonate coating buffer pH 9.6 overnight at 4° C. Control wells were coated with human transferrin. Next, the plates were blocked with 3% milk powder in PBS for 1 hour at room temperature. Then, hybridoma tissue culture supernatants were plated at 100 μL / well for 1 hour at 37° C. with shaking. The secondary antibody (1:10,000 goat anti-mouse IgG / IgM(H+L)-HRP) was applied at 100 μL / well for 1.5 hours at room temperature with shaking. TMB substrate was added at 50 μL / well for 5 minutes at room temperature in the dark. The reaction was stopped with 50 μL / well 1M HCl and absorbance readings were taken at a wavelength of 450 nm.

[0267]Four hybridoma supernatants containing the an...

example 3

Anti-C1q Antibodies Inhibit Complement-Mediated Hemolysis

[0275]Anti-C1q antibodies were tested in human and rodent hemolytic assays (CH50) for their ability to neutralize C1q and block its activation of the downstream complement cascade. CH50 assays were conducted essentially as described in Current Protocols in Immunology (1994) Supplement 9 Unit 13.1. In brief, 5 microliters (μl) of human serum (Cedarlane, Burlington, N.C.), 0.625 μl of Wistar rat serum, or 2.5 μl of C57B1 / 6 mouse serum was diluted to 50 μl of GVB buffer (Cedarlane, Burlington, N.C.) and added to 50 μl of the monoclonal antibodies (1 μg) diluted in GVB buffer. The antibody:serum mixture was pre-incubated for 30 minutes on ice and then added to 100 μl of EA cells (2×108 / ml) for rat and human assays, and 4×107 / ml for mouse assays. The EA cells were generated exactly as specified in Current Protocols using Sheeps blood in Alsever's (Cedarlane Cat #CL2581) and hemolysin (Cedalane Cat #CL9000). The EA cells, serum and ...

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Abstract

This invention relates generally to methods of treatment for neurodegenerative diseases such as Alzheimer's disease, Alzheimer's-related diseases, and Huntington's disease, and more specifically to methods involving the inhibition of the classical pathway of complement activation.

Description

CROSS REFERENCES TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 844,369, filed Jul. 9, 2013, and U.S. Provisional Application No. 61 / 871,813, filed Aug. 29, 2013, each of which is hereby incorporated by reference in its entirety.SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE[0002]The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 717192000840SeqList.txt, date recorded: Jul. 9, 2014, size: 13 KB).BACKGROUND[0003]1. Field[0004]This invention relates generally to methods of treatment for neurodegenerative diseases such as Alzheimer's disease, Alzheimer's-related diseases, and Huntington's disease, and more specifically to methods involving the inhibition of the classical pathway of complement activation.[0005]2. Description of Related Art[0006]A neurodegenerative disease is a disease involving cogniti...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/18C07K16/40
CPCC07K16/18C07K16/40C07K2317/56C07K2317/14C07K2317/20A61K2039/507C07K2317/92C07K2317/76C07K2317/31C07K2317/94C07K2317/33C07K2317/34A61K2039/505A61P1/04A61P11/00A61P11/06A61P13/12A61P17/00A61P21/00A61P21/04A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P27/06A61P29/00A61P3/00A61P3/04A61P37/02A61P37/06A61P7/00A61P7/06A61P9/10A61P3/10A61K49/0004C07K2317/24C07K2317/54C07K2317/55C07K2317/734G01N33/56966G01N2333/4716
Inventor ROSENTHAL, ARNONLEVITEN, MICHAELSTEVENS, BETH A.HONG, SOYONWILTON, DANIEL
Owner ANNEXON
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