Antibodies specific for soluble amyloid beta peptide protofibrils and uses thereof
Inventors
GELLERFORS PAER, null • Gellerfors, Pär • Lannfelt, Lars
Assignees
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Publication Number
US-8106164-B2
Publication Date
2012-01-31
Expiration Date
Abstract
The invention pertains to the development of antibodies that specifically bind amyloid beta protein (Abeta) in its protofibril conformation. The invention also comprises methods of using anti-Abeta protofibril antibodies to diagnose or treat Alzheimer's disease, Down's syndrome Lewybody dementia, vascular dementia, and other neurodegenerative disorders. Furthermore, the invention pertains to the use of anti-Abeta protofibril antibodies to screen and identify substances that will modulate protofibril activity or formation in vitro or in vivo. The invention also pertains to methods for synthesising pure Abeta protofibril antigens as well as to a method for stabilising Abeta protofibrils antigens as well as to a method for stabilising Abeta protofibrils.
Core Innovation
The invention concerns isolated monoclonal antibodies or antigen-binding fragments that specifically bind wild-type Aβ42/40 protofibril and Aβ42/40arc protofibril in a conformation-specific manner. The antibodies have no or little cross-reactivity to Aβ42/40 monomers.
The described antibodies show low or no cross-reactivity to Aβ monomers and fibrils while retaining protofibril detection capability for wild-type Aβ42/40 protofibrils and Aβ42/40arc protofibrils. Example mAb258 demonstrates protofibril detection with minimal monomer and fibril binding.
The invention further provides production of highly pure stabilized Aβ protofibril antigens, including wild-type and Arctic variants, and assessment of protofibril purity and binding using ELISA. The conformation-specific protofibril targeting and low monomer and fibril cross-reactivity are linked to avoiding side effects associated with fibril cross-reactivity.
Claims Coverage
The claim set identifies one independent claim centered on antibody binding to protofibrils with a specified cross-reactivity profile. Several dependent claims further define antibody format, antigen input, and use.
Monoclonal antibody binding protofibril conformation with no or little monomer cross-reactivity
An isolated monoclonal antibody or antigen-binding fragment that binds wild-type Aβ42/40 protofibril and Aβ42/40arc protofibril, and has no or little cross-reactivity to Aβ42/40 monomers.
Immunizing and screening with greater than 95% pure Aβ42/40arc protofibrils
The antibody is produced by immunizing and screening using at least greater than 95% pure Aβ42/40arc protofibrils.
Immunizing and screening with greater than 95% pure Aβ42/40 protofibrils
The antibody is produced by immunizing and screening using at least greater than 95% pure Aβ42/40 protofibrils.
Humanized antibody
The antibody described is humanized.
Protofibril conformation-specific antibody or antibody fragment
The antibody is a protofibril conformation-specific antibody or an antibody fragment.
Treating Alzheimer’s disease by administration to a patient
Treating Alzheimer’s disease by administering the antibody to a patient who has or is suspected of having Alzheimer’s disease.
Overall, the claims center on monoclonal antibodies that bind wild-type Aβ42/40 protofibrils and Aβ42/40arc protofibrils with no or little cross-reactivity to Aβ42/40 monomers, with dependent claim refinements covering high-purity protofibril-based immunogen and screening inputs, humanized and protofibril conformation-specific formats, and administration for Alzheimer’s disease.
Stated Advantages
Low or no cross-reactivity to Aβ42/40 monomers and fibrils.
Avoidance of side effects associated with fibril cross-reactivity.
Documented Applications
Diagnosing multiple neurodegenerative diseases, including Alzheimer’s disease, Down’s syndrome, Lewybody dementia, and vascular dementia.
Biomarker quantitation in biological fluids.
Imaging with labeled antibodies.
In vitro and in vivo screening of drug candidates by measuring protofibril levels or activity.
Treating Alzheimer’s disease by administering the antibody to a patient who has or is suspected of having Alzheimer’s disease.
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