HLA-A24 agonist epitopes of MUC1-C oncoprotein and compositions and methods of use
Inventors
Schlom, Jeffrey • Tsang, Kwong-Yok
Assignees
US Department of Health and Human Services
Publication Number
US-12325731-B2
Publication Date
2025-06-10
Expiration Date
2034-10-22
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Abstract
The invention provides a human cytotoxic T lymphocyte (CTL) agonist epitope from the C-terminal subunit of mucin 1 (MUC1-C), which can be used as a peptide, polypeptide (protein), and/or in vaccine or other composition for the prevention or therapy of cancer. The invention further provides a nucleic acid encoding the peptide, protein, or polypeptide, a vector comprising the nucleic acid, a cell comprising the peptide, polypeptide, nucleic acid, or vector, and compositions thereof.
Core Innovation
The invention provides human cytotoxic T lymphocyte (CTL) agonist epitopes derived from the C-terminal subunit of the mucin 1 (MUC1-C) oncoprotein, particularly peptides with the amino acid sequences of SEQ ID NO: 1 (KYHPMSEYAL) and SEQ ID NO: 2 (KYTNPAVAL). These peptides and polypeptides comprising these sequences or fragments thereof with agonist substitutions can be used in vaccines and immunotherapeutic compositions for the prevention and treatment of cancers expressing or overexpressing MUC1. The invention further encompasses nucleic acids encoding these peptides or polypeptides, expression vectors, recombinant cells including yeast cells expressing these antigens, and yeast-based immunotherapeutic compositions that include these MUC1 agonist epitopes.
The problem addressed lies in the need for enhanced and specific CTL epitopes of MUC1-C to elicit stronger T-cell activation and tumor cell killing compared to native epitopes. While the MUC1 N-terminal subunit (MUC1-N) epitopes, particularly the VNTR region, have been explored as vaccine candidates, identification of agonist epitopes in the MUC1-C domain with superior immunogenicity and tumor recognition has been lacking. Existing peptides may stimulate T-cell cytokine production but fail to induce tumor cell lysis. The invention solves this problem by identifying and providing enhancer agonist epitopes of MUC1-C that improve T cell activation and recognition, thereby providing novel immunotherapeutic tools to combat MUC1-expressing tumors and improve cancer immunotherapy outcomes.
Claims Coverage
The independent claim discloses a peptide comprising the amino acid sequence of SEQ ID NO: 16, and subsequent claims cover immunotherapeutic compositions including this peptide and carriers.
Peptide comprising the amino acid sequence of SEQ ID NO: 16
A peptide consisting of the amino acid sequence of SEQ ID NO: 16, which is a fusion protein including a MUC1 antigen with multiple agonist substitutions and an inactivating mutation.
Immunotherapeutic composition including the peptide and pharmaceutically acceptable carrier
An immunotherapeutic composition comprising the peptide of SEQ ID NO: 16 and a pharmaceutically acceptable carrier.
Optional inclusion of adjuvants or cytokines in the immunotherapeutic composition
The immunotherapeutic composition can further include an adjuvant or a cytokine to enhance immune response.
Inclusion of cellular compositions including whole cells or lysates
The immunotherapeutic composition may comprise cellular compositions such as whole cells, cell lysates, or disrupted cells.
Incorporation of yeast or yeast expressing the peptide
The immunotherapeutic composition may include yeast, specifically Saccharomyces cerevisiae, expressing the peptide.
Production of peptide by culturing whole yeast at neutral to slightly alkaline pH
The peptide is produced by culturing whole yeast expressing a nucleic acid encoding the peptide in a medium maintained at a pH between 5.5 and 8.
The claims cover a peptide of SEQ ID NO: 16 representing a MUC1 agonist antigen fusion protein and immunotherapeutic compositions containing this peptide with various carriers and adjuvants, including yeast-based formulations with controlled expression conditions. These inventive features provide novel therapeutic compositions for cancer treatment.
Stated Advantages
The agonist epitopes enhance cytotoxic T lymphocyte activation leading to more efficient lysis of human tumor cells expressing native MUC1.
The peptides and polypeptides can induce stronger and more specific T-cell responses compared to native epitopes.
The yeast-based immunotherapeutic compositions can induce both CD4+ and CD8+ T-cell-mediated immune responses and modulate regulatory T cells.
The agonist epitopes enable the stimulation of T cells in vitro and in vivo, facilitating adoptive T-cell therapy and vaccine development.
Culturing yeast under neutral pH conditions improves cell wall pliability, antigen exposure, and promotes enhanced immune responses.
Recombinant expression in MVA or other viral vectors elicits strong immune responses with favorable safety profiles.
Documented Applications
Prevention and therapeutic treatment of MUC1-expressing cancers, including ovarian, breast, colorectal, lung, prostate, pancreatic, and hematologic malignancies.
Use as peptides, polypeptides, or proteins in vaccine compositions to enhance anti-cancer immune responses.
Adoptive T cell therapy applications via ex vivo stimulation of lymphocytes or dendritic cells with the peptides or compositions.
Yeast-based immunotherapy compositions used alone or in combination with other anticancer therapies, including chemotherapy, radiation, and targeted treatments.
Use of recombinant viral vectors (e.g., poxvirus, MVA) encoding the MUC1 agonist epitopes in prime-boost vaccination regimens.
Activation of MUC1-specific HLAA24-restricted T cells to produce cytokines such as IFN-γ for immune therapy.
Clinical application demonstrated by a phase 1 clinical trial for patients with MUC1-positive tumors assessing safety, immunogenicity, and clinical activity.
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