Protofibril selective antibodies and the use thereof
Inventors
Gellerfors, Pär • Lannfelt, Lars • Sehlin, Dag • Ekholm Pettersson, Frida • Englund, Hillevi
Assignees
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Publication Number
US-9034334-B2
Publication Date
2015-05-19
Expiration Date
Abstract
The invention relates to an isolated antibody, or fragment thereof, having high affinity for human Aβ protofibrils. The invention further relates to compositions that include the antibody, or a fragment thereof, and a pharmaceutically acceptable buffer. The invention further relates to a method of preventing or treating Alzheimer's disease, which includes the step of administering to a patient having or suspected of having Alzheimer's disease such an antibody, or fragment thereof or a composition that includes the antibody or a fragment thereof.
Core Innovation
The invention relates to human Aβ protofibril selective antibodies, including humanized immunoglobulin variants and an isolated IgG antibody such as mAb158, engineered to retain Fc receptor binding while reducing C1q/complement activation. The antibodies have high affinity for human Aβ protofibrils associated with an Alzheimer disease epitope, and Fc-domain modifications and/or glycosylation changes reduce inflammatory risk while maintaining Fc receptor mediated functions.
The document describes humanized immunoglobulin variants, including 158RHAss and related variants such as 158RKA variants, with detailed immunoglobulin sequence information. The sequence information includes specific CDR1, CDR2, and CDR3 amino-acid sequences for both VH and VL regions, together with associated DNA and protein sequence tables, splice-site predictions, and mutations.
The partial content further provides sequence information for humanized antibody frameworks and related components, including reference to 158 VK/VH frameworks and scFv variants. The documented tables include sequence identifiers and features such as splice donor sites and a stated VK/VH signal peptide (A19), supporting the presented variant set used for measuring Aβ protofibrils.
Claims Coverage
The partial content identifies one independent claim directed to measuring Aβ protofibrils in a mammal. Dependent claims further refine the labeling agent and optionally narrow the use to specific diagnostic indications (Alzheimer’s disease and Down’s syndrome).
Measuring human Aβ protofibrils with a labeled, high-affinity protofibril-selective antibody
A method of measuring Aβ protofibrils in a mammal by providing a labeled antibody or fragment thereof that is selective and has high affinity for human Aβ protofibrils, where the labeled antibody or fragment comprises defined six CDR regions (VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, VL-CDR3), administering the labeled antibody or fragment to a mammal comprising or suspected of comprising Aβ protofibrils, and measuring the concentration of a complex formed between the Aβ protofibril and the antibody or fragment by measuring a signal generated by the agent.
Six CDR regions defined in the labeled antibody or fragment
The labeled antibody or fragment in its six CDR regions comprises specified VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 amino-acid sequences, where the antibody or fragment is labeled with an agent that generates a measurable signal.
Radioactive ligand as the measurable-signal label
The method provides that the labeled antibody or fragment is labeled with an agent comprising a radioactive ligand to generate the measurable signal.
Radioactive ligand isotopes for the label
The method uses a radioactive ligand selected from I-131, C-14, H-3, or Gallium-68.
Measuring for diagnosing Alzheimer's disease or Down's syndrome
The measuring step is used to diagnose Alzheimer's disease or Down's syndrome.
The independent claim centers on measuring Aβ protofibril concentration in a mammal using a labeled, selective high-affinity antibody or fragment whose six CDR regions are specified, with signal readout from a label that forms a measurable complex. Dependent claims specify radioactive ligands, including particular nuclides, and narrow the measurement’s purpose to diagnoses of Alzheimer’s disease or Down’s syndrome.
Stated Advantages
Clears Aβ protofibrils while reducing inflammatory risk by reducing C1q/complement activation.
Supports therapeutic rationale for Alzheimer’s disease and Down’s syndrome.
Enables detection of very low Aβ protofibril levels, including pM-range detection, for diagnostic measurement.
Reduces plaques and reduced total Aβ/protofibril levels after antibody administration in described animal-model findings.
Documented Applications
Therapeutic use for clearing Aβ protofibrils in Alzheimer’s disease, with reduced inflammatory risk.
Therapeutic rationale also described for Down’s syndrome.
Diagnostic measurement of Aβ protofibrils in a mammal, including diagnosis of Alzheimer’s disease.
Diagnostic measurement of Aβ protofibrils in a mammal, including diagnosis of Down’s syndrome.
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