Colon and pancreas cancer specific antigens and antibodies
Inventors
Du, Xiulian • Luka, Janos • Stafford, Lewis Joe • Semenuk, Mark • Wang, Xue-Ping • Kantor, Judith • Bristol, Andrew
Assignees
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Publication Number
US-11345733-B2
Publication Date
2022-05-31
Expiration Date
Abstract
This invention relates to NPC-1 antigen on the MUC5AC protein and 16C3 antigen on CEACAM5 and CEACAM6 proteins, and 31.1 epitope on the A33 protein are differentially expressed in cancers including, lung cancer, ovarian cancer, pancreas cancer, breast cancer, and colon cancer, and diagnostic and therapeutic usages. Further, NPC-1, 16C3, and/or 31.1 epitope specific antibodies and diagnostic and therapeutic methods of use.
Core Innovation
The invention concerns making an antibody by administering a pharmaceutical composition to a mammalian subject that comprises an isolated MUC5AC polypeptide comprising the NPC-1 epitope. The NPC-1 epitope comprises a glycosylation variant (glycotope) expressed by tumor cells, and the isolated polypeptide is a MUC5AC polypeptide. The NPC-1 epitope is mapped to MUC5AC tandem repeat regions and includes defined sequence fragments, including a region corresponding to SEQ ID NO: 36.
The isolated polypeptide comprises at least 90% identity to SEQ ID NO: 36 or SEQ ID NO: 37, or a sequence corresponding to defined MUC5AC-long tandem repeat residue ranges, including residues 1-151, 1-289, 1-306, or 1-338. The disclosure associates the NPC-1 epitope with glycan-processing sensitivity, including neuraminidase sensitivity, periodate oxidation, and sensitivity to sialylation patterns.
The invention further reports functional binding and specificity characterization tied to glycotope features. It links the defined MUC5AC-derived NPC-1 epitope polypeptides to antigen and antibody reagents in cancer contexts involving colon and pancreas, among other cancers.
Claims Coverage
The independent claims cover a method of making an antibody by administering a pharmaceutical composition containing an isolated MUC5AC polypeptide that presents the NPC-1 epitope as a glycosylation variant (glycotope) expressed by tumor cells. The main inventive features are the defined MUC5AC sequence selections, including identity to SEQ ID NO: 36 or SEQ ID NO: 37 and defined residue ranges from MUC5AC-long.
Glycosylation variant NPC-1 epitope presented by MUC5AC polypeptide
Administering a pharmaceutical composition comprising an isolated polypeptide comprising the NPC-1 epitope to a mammalian subject, wherein the NPC-1 epitope comprises a glycosylation variant (glycotope) expressed by tumor cells, and wherein the isolated polypeptide is a MUC5AC polypeptide.
Isolated MUC5AC polypeptide with at least 90% identity to SEQ ID NO: 36
Wherein said isolated polypeptide comprises a polypeptide having at least 90% identity to SEQ ID NO: 36, and wherein said isolated polypeptide is a MUC5AC polypeptide.
Isolated MUC5AC polypeptide with at least 90% identity to SEQ ID NO: 37
Wherein said isolated polypeptide comprises a polypeptide having at least 90% identity to SEQ ID NO: 37, and wherein said isolated polypeptide is a MUC5AC polypeptide.
Selected residue ranges from MUC5AC-long tandem repeat region for NPC-1 epitope
Administering a pharmaceutical composition comprising an isolated polypeptide comprising the NPC-1 epitope, wherein the isolated polypeptide comprises residues 1-289, residues 1-306, residues 1-338, or residues 1-151 of the tandem repeat region of MUC5AC-long.
The claim set covers antibody-making methods using a tumor-cell expressed NPC-1 glycosylation variant glycotope presented by MUC5AC polypeptides, with antigen definition anchored either to at least 90% identity to SEQ ID NO: 36 or SEQ ID NO: 37, or to specific residue-length selections from the MUC5AC-long tandem repeat region.
Stated Advantages
Not explicitly described in patent.
Documented Applications
In vitro ADCC against multiple pancreatic and colorectal tumor lines using PBMC effectors.
In vivo xenograft tumor growth inhibition in tumor models including AsPC-1, CFPAC-1, and LS174T.
Tumor-localized accumulation and limited toxicity supported by preliminary PK/toxicity/biodistribution.
Epitope/glycotope characterization for NPC-1C, including thermolysin fragmentation and glycan sensitivity mapping (neuraminidase and periodate oxidation sensitivity) and competitive behavior in immunoassay.
Fecal ELISA detection of NPC-1 antigen using stool-based fecal samples.
Development/uses of an anti-idiotype antibody 4B6.
Diagnostic and therapeutic use across cancer contexts involving colon and pancreas, among other cancers.
Patient serum antigen detection.
Antibody-related anti-tumor activity and biodistribution studies using labeled antibodies and antibody formats.
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