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Publication Number
US-11078245-B2
Publication Date
2021-08-03
Expiration Date
Abstract
The invention relates to a peptidomimetic of an NPC-1 epitope on the MUC5AC protein which is differentially expressed in pancreatic and colorectal cancer, and diagnostic and therapeutic usages. Further, antibodies that selectively bind the NPC-1 epitope peptidomimetics and may be used in diagnostic and therapeutic methods.
Core Innovation
The disclosure relates to MUC5AC NPC-1 epitope peptidomimetics, including isolated polypeptides having at least 80% identity to the amino acid sequence SLEPEX1DWX2FRYX3NY (SEQ ID NO: 3), wherein X1 is E or D; X2 is W or Y; and X3 is T or I, or any one of the amino acid sequences of SEQ ID NOs: 6 or 7. The document further includes variants that maintain antigenicity of the NPC-1 epitope peptidomimetic.
The invention covers nucleic acids encoding the polypeptides, together with recombinant fusion protein constructs, expression vectors, host cell production approaches, selection markers, cleavable linkers, and related processing elements. It also frames the nucleic acids with transcriptional starts and with nucleic-acid cloning and expression approaches.
The disclosure further includes NPC-1 epitope peptidomimetics in compositions, diagnostic kits, antibodies or antigen-binding fragments selectively binding the peptidomimetics, and conjugates with labels, effector groups, cytotoxic agents, carbohydrates, and carriers. The document also describes identification and characterization of the NPC-1 epitope within the MUC5AC tandem repeat region, including thermolysin digestion fragments, neuraminidase sensitivity, glycan-dependent behavior, imaging and tissue staining correlation, and anti-tumor activity in a xenograft tumor model.
Claims Coverage
The independent claim set includes one isolated polypeptide defined by sequence identity to a specific SLEPEX-derived motif with allowable substitutions, with dependent claims adding nucleic acids encoding the polypeptide, cancer treatment by eliciting an anti-cancer immune response, dendritic-cell activation, and a selectable multi-component conjugate. In total, the claims cover five inventive features.
Isolated polypeptide with defined SLEPEX-derived motif identity
An isolated polypeptide comprising a polypeptide having at least 80% identity to the amino acid sequence SLEPEX1DWX2FRYX3NY (SEQ ID NO: 3), wherein X1 is E or D; X2 is W or Y; and X3 is T or I; or any one of the amino acid sequences of SEQ ID NOs: 6 or 7.
Isolated nucleic acid encoding the SLEPEX-defined polypeptide
An isolated nucleic acid that encodes a polypeptide as defined by claim 1.
Cancer treatment by eliciting an anti-cancer immune response
Treating cancer in a subject by administering an effective amount of a polypeptide as defined in claim 1 to elicit an anti-cancer immune response.
Dendritic cell activation by ex vivo contact with the polypeptide
Activating a patient’s dendritic cells by removing them, contacting them ex vivo with an effective amount of the polypeptide of claim 1, and reinfusing the activated dendritic cells back into the patient.
Selectable multi-component conjugate including cytotoxic agents and diagnostic or imaging labels
A conjugate in which the cytotoxic agent, label, carbohydrate, and carrier are each selected from specified alternative groups.
The claims focus on an isolated SLEPEX-derived polypeptide and its encoding nucleic acid, with additional coverage for cancer treatment, dendritic-cell activation, and multi-component conjugates that include cytotoxic agents and labels.
Stated Advantages
Elicits an anti-cancer immune response for treating cancer.
Activates dendritic cells in a patient through ex vivo activation with the polypeptide.
Enables use of conjugates incorporating cytotoxic agents and selected labels, carbohydrates, and carriers.
Tumor-specific glycotope binding for use in cancer diagnosis and therapy, including colon and pancreatic cancers and related cancers.
Selective binding by antibodies or antigen-binding fragments to the NPC-1 epitope peptidomimetics.
Diagnostic capability including imaging and tissue staining correlation.
Anti-tumor activity in a xenograft tumor model.
Documented Applications
Cancer treatment in a subject using a polypeptide to elicit an anti-cancer immune response.
Dendritic-cell activation via ex vivo contact with the polypeptide followed by reinfusion into the patient.
Diagnostic detection and immunoassay-based detection framed around NPC-1 epitope peptidomimetics and antibodies, including imaging modalities and biomarker panels.
Fecal biomarker measurement using fecal sample ELISA for diagnostic detection.
Cancer diagnosis for colon cancer and pancreas cancer using NPC-1 epitope peptidomimetics, including diagnostic assay formats and imaging.
Cancer therapy, including eliciting an anti-cancer immune response by administering an effective amount of the polypeptide in a subject.
Tumor targeting and evaluation in a xenograft tumor model with related reagents.
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