Monoclonal antibodies that target pathological assemblies of amyloid β (Abeta)
Inventors
Lambert, Mary P • Velasco, Pauline T. • Chang, Lei • Viola, Kirsten L. • Fernandez, Sara J. • Lacor, Pascale N. • Khuon, Daliya • Gong, Yuesong • Klein, William L. • Krafft, Grant A.
Assignees
Merck Sharp and Dohme LLC • Northwestern University • Acumen Pharmaceuticals Inc
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Publication Number
US-8507206-B2
Publication Date
2013-08-13
Expiration Date
Abstract
Disclosed herein are antibodies that bind with high specificity to soluble oligomers of amyloid β (Abeta) and methods of employing those antibodies. The antibodies are able to distinguish between Alzheimer's Disease (AD) and control human brain extracts. The antibodies identify endogenous Abeta oligomers in AD brain slices and also bind to Abeta oligomers on cultured hippocampal cells. The antibodies neutralize endogenous Abeta oligomers and Abeta oligomers produced in solution.
Core Innovation
The disclosure relates to monoclonal antibodies that selectively bind soluble amyloid β (Aβ) oligomers/ADDLs while largely avoiding Aβ monomers and fibrils. The antibodies discriminate Alzheimer’s disease versus control human brain extracts and produce immunolabeling patterns in AD brain sections.
One antibody is characterized as oligomer-selective, with preferential binding for Aβ 12–24mers over Aβ monomers, and minimal monomer affinity. The disclosed epitope is conformational and dependent on Aβ1–28, with binding blocked by Aβ1–28 but not by shorter linear peptides spanning Aβ1–42.
The disclosure further describes an antibody-generated diagnostic framework using ADDL-selective monoclonals to assay ADDLs in brain extracts, brain sections, and CSF. Reported readouts include immunohistochemistry and immunoassay formats such as ELISA and cell hot spot immunofluorescence.
Claims Coverage
The provided set contains one independent claim. The claim centers on a neutralization method driven by a monoclonal antibody with specified oligomer selectivity and binding inhibition to cells, yielding neutralization of soluble Aβ oligomer binding.
Monoclonal antibody oligomer selectivity for Abeta 1-42 12-24 oligomers
A monoclonal antibody that selectively binds soluble 12–24 oligomers of Abeta 1-42 over trimers and tetramers of Abeta 1-42.
Inhibits binding of soluble Abeta oligomers to cells
The monoclonal antibody inhibits binding of soluble Abeta oligomers to cells.
Neutralizes binding of soluble Abeta oligomers to cells by contacting
Neutralizing is achieved by contacting soluble Abeta oligomers with the monoclonal antibody to neutralize soluble Abeta oligomer binding to cells.
The independent claim defines a method where soluble Abeta oligomers are contacted with a monoclonal antibody that selectively binds Abeta 1-42 12–24 oligomers over trimers and tetramers and inhibits binding of soluble Abeta oligomers to cells, thereby neutralizing the binding.
Stated Advantages
Neutralizes binding of soluble Aβ oligomers to cells.
Selectively binds soluble 12–24 oligomers of Aβ1–42 over trimers and tetramers of Aβ1–42.
Documented Applications
Discriminating AD versus control human brain extracts and producing immunolabeling patterns in AD brain sections.
Immunolabeling and assaying ADDLs in brain extracts, brain sections, and CSF.
Measuring ADDLs in CSF for correlations with AD pathology and cognitive status.
Using ADDL-selective monoclonals in immunohistochemistry and immunoassays, including ELISA and cell hot spot immunofluorescence, as part of a diagnostic framework.
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