Humanized antibodies binding to amyloid-beta (A-beta)

Inventors

Cashman, Neil R. • Plotkin, Steven S. • Kaplan, Johanne • Silverman, Judith Maxwell • Gibbs, Ebrima

Assignees

University of British Columbia • Promis Neurosciences Inc

Abstract

The disclosure pertains to antibodies that bind A-beta oligomers and methods of making and using said antibodies. Also provided are chimeric or humanized antibodies, including antibodies having CDRs in Table 2 and/or having a sequence as set forth in Table 4B or a sequence with at least 50% sequence identity thereto optionally wherein the CDR amino acid sequences are as set for forth in SEQ ID Nos: 74-79. Also provided are methods and uses thereof as well as kits comprising said antibodies.

Core Innovation

The invention relates to humanized antibodies or antigen binding fragments thereof that bind amyloid-beta (A-beta). The antibodies are defined by specific heavy chain variable region amino acid sequences identified by SEQ ID NOs, paired with specific light chain variable region amino acid sequences identified by SEQ ID NOs.

The disclosed antibody designs are conformationally selective for A-beta oligomers, with reduced or non-negligible plaque (fibril) binding compared with binding to linear HHQK (SEQ ID NO:7). Reported binding and functional support includes SPR binding to A-beta oligomers and preference for low-molecular-weight (LMW) toxic oligomer-enriched brain fractions versus other fractions.

The document further describes antibody formats and associated constructs that include antigen-binding fragments such as Fab, F(ab')2, dimers, and multimers, and full antibody isotypes including IgG1 and IgG4 (S241P hinge variant). It also discloses nucleic acids, vectors, and cells for encoding and expressing the antibodies, and kit formats for detection, including detectable labels and positron-emitting radionuclide labels for PET imaging.

Claims Coverage

The independent claim set in the provided excerpt includes 1 independent claim, which defines a humanized antibody or antigen binding fragment by specific heavy-chain and light-chain variable region amino acid sequences. The claim coverage includes dependent refinements that further restrict SEQ ID pairings, nucleotide-encoded variants, antibody format and isotype, and label/imaging features.

Overall, the claim coverage centers on a humanized antibody or antigen-binding fragment binding amyloid-beta defined by particular heavy-chain and light-chain variable region sequences, with dependent claims refining the specific SEQ ID pairings, specifying encoded sequence variants, restricting fragment formats and isotype, and adding a detectable label based on a positron-emitting radionuclide for imaging.

Stated Advantages

Documented Applications