Humanized monoclonal antibodies and methods of use for the diagnosis and treatment of colon and pancreas cancer
Inventors
Wang, Xue-Ping • ARLEN, Philip M.
Assignees
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Publication Number
US-11505604-B2
Publication Date
2022-11-22
Expiration Date
Abstract
This invention relates to humanized antibodies that selectively bind the 31.1 epitope on the A33 protein differentially expressed in cancers including, lung cancer, ovarian cancer, pancreas cancer, breast cancer, and colon cancer, and diagnostic and therapeutic usages.
Core Innovation
The invention relates to isolated nucleic acids that encode an antibody or fragment thereof that binds to an A33 antigen. The antibody comprises defined heavy chain variable regions and light chain variable regions, including amino acids 1 to 118 of SEQ ID NO:74, 75, 76, or 77 and amino acids 1 to 107 of SEQ ID NO:84, 85, 86, or 87, together with corresponding heavy CDR sequences and light CDR sequences. The described antibody family includes humanized 31.1 (NEO-300) monoclonal antibodies and related cdr31.1-HC, cdr31.1-LC, abb31.1-LC, sdr31.1-LC, or ven31.1-LC variable region pairings.
The disclosed antibodies selectively bind an A33 antigen via a non-linear 31.1 epitope. The epitope is conformational and protein/disulfide dependent, with reduced-condition binding loss and detergent sensitivity described, and epitope mapping and phage-display indication of epitope location further support the non-linear nature of the 31.1 epitope.
The patent states that characterization and in vivo tumor progression inhibition is observed with NEO-301 and NEO-302 antibodies directed to the A33/31.1 epitope. The described outcomes include slowing growth, killing tumor cells, and promoting regression, and the disclosure reports binding specificity and functional effects associated with A33 binding, including ADCC-related activity and tumor growth suppression results.
Claims Coverage
The provided claim coverage centers on isolated nucleic acids encoding A33-binding antibodies with specified heavy and light variable regions, and includes additional inventive features for functional potentiation, sequence-specific binding, and antibody production. Six inventive features are identified across the claim set.
A33-binding variable heavy and light chains defined by SEQ ID NOs
An isolated nucleic acid that encodes an antibody or fragment thereof that binds to an A33 antigen, wherein the antibody comprises a heavy chain variable region comprising amino acids 1 to 118 of SEQ ID NO:74, 75, 76, or 77 and a light chain variable region comprising amino acids 1 to 107 of SEQ ID NO:84, 85, 86, or 87.
Potentiation of ADCC
The isolated nucleic acid of claim 1, wherein said antibody or fragment thereof potentiates ADCC.
Potentiation of CDC
The isolated nucleic acid of claim 1, wherein said antibody or fragment thereof potentiates CDC.
Specific binding to amino acid sequences defined by SEQ ID NOs
The isolated nucleic acid of claim 1, wherein said antibody or fragment thereof specifically binds the amino acid sequence of SEQ ID NOs: 10, 11, 12, or 13.
Specific heavy/light variable region pairing using SEQ ID NOs 77 and 87
The isolated nucleic acid of claim 1, wherein the antibody or antibody fragment comprises a heavy chain variable chain comprising amino acids 1 to 118 of SEQ ID NO:77 and a light chain variable chain comprising amino acids 1 to 107 of SEQ ID NO:87.
Making an A33-binding antibody by expressing the nucleic acid
A method for making an antibody or an antibody fragment that binds to an A33 antigen, the method comprising expressing the isolated nucleic acid of claim 1.
Overall, the claim coverage is centered on isolated nucleic acids encoding A33-binding antibodies defined by particular heavy- and light-chain variable regions, with further refinements that specify particular sequence-binding and functional potentiation of ADCC and CDC, and a method aspect covering antibody production by expressing the nucleic acid.
Stated Advantages
Provides nucleic acids encoding A33-binding antibodies or fragments with specified heavy- and light-chain variable regions.
Supports binding specificity to defined A33-related targets and selective binding to a non-linear 31.1 epitope on the A33 antigen.
Describes functional activity associated with A33 binding, including reported ADCC and tumor growth suppression, slowing growth, killing tumor cells, and promoting regression.
Enables epitope detection in patient samples.
Provides diagnostic kit and diagnostic/epitope detection use in labeled or solid-support formats.
Documented Applications
Diagnostic and immunoassay detection of A33 in patient samples using labeled antibody formats and immunoassay formats described in the document, including ELISA, RIA, Western, sandwich assays, lateral flow, and immunohistochemistry.
Imaging applications using labeled antibody formats for imaging, including PET, SPECT, MRI, CT, US, and a SQUID technique.
Biomarker and genetic diagnosis approaches described in the document, including diagnostic biomarkers and NAT-based genetic diagnosis.
Therapeutic use, including slowing tumor growth, killing tumor cells, and promoting regression, associated with NEO-301 and NEO-302 antibodies.
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