Nucleic acids encoding HLA-A24 agonist epitopes of MUC1-C oncoprotein
Inventors
Schlom, Jeffrey • Tsang, Kwong-Yok
Assignees
US Department of Health and Human Services
Publication Number
US-10508141-B2
Publication Date
2019-12-17
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 from the C-terminal subunit of mucin 1 (MUC1-C), which can be used as peptides, polypeptides (proteins), and/or in vaccines or other compositions for the prevention or therapy of cancer. It further provides nucleic acids encoding these peptides or polypeptides, vectors comprising the nucleic acids, cells comprising the peptides, polypeptides, nucleic acids, or vectors, and compositions thereof. Specifically, peptides comprising the amino acid sequences of SEQ ID NO: 1 or SEQ ID NO: 2 and related polypeptides and fusion proteins containing these epitopes are disclosed.
MUC1 is a type I membrane glycoprotein composed of two subunits: a large N-terminal subunit (MUC1-N) and a smaller C-terminal subunit (MUC1-C). The MUC1-C subunit contains domains implicated in oncogenic signaling and cancer progression, including a cytoplasmic tail interacting with signaling proteins. MUC1-C acts as an oncogene, promoting transformation, increased growth, chemoresistance, and metastasis. Prior vaccines have primarily targeted the VNTR region of MUC1-N but have had limited efficacy. There is a need to identify new specific CTL epitopes and enhancer agonist peptides from MUC1-C to improve therapeutic approaches for cancers expressing MUC1.
The invention addresses this need by identifying MUC1-C specific CTL agonist epitopes (SEQ ID NO: 1 and SEQ ID NO: 2) and producing compositions including peptides, polypeptides, nucleic acids, vectors, and yeast-based immunotherapeutic compositions that incorporate these epitopes. Methods of enhancing immune responses against MUC1-expressing cancers via administration of these compositions are described. The invention also encompasses methods of inhibiting, treating, preventing, or delaying metastasis and progression of MUC1-expressing cancers in subjects. Additionally, adoptive T cell therapies using T cells stimulated ex vivo with these peptides or compositions are disclosed.
Claims Coverage
The patent claims comprise independent claims directed to isolated nucleic acids encoding peptides comprising SEQ ID NO:1 or SEQ ID NO:2, vectors comprising these nucleic acids, cells comprising these nucleic acids, and compositions comprising these nucleic acids with pharmaceutically acceptable carriers.
Nucleic acid encoding MUC1-C agonist epitopes
An isolated nucleic acid encoding a peptide comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2, representing human CTL agonist epitopes derived from the C-terminal subunit of MUC1.
Vector comprising nucleic acid encoding MUC1-C agonist epitopes
An isolated vector comprising the nucleic acid encoding the peptide of SEQ ID NO:1 or SEQ ID NO:2, enabling expression of the MUC1 CTL agonist epitope.
Cell comprising nucleic acid encoding MUC1-C agonist epitopes
An isolated cell, including human cells or antigen presenting or tumor cells, comprising the nucleic acid encoding the peptide of SEQ ID NO:1 or SEQ ID NO:2.
Composition comprising nucleic acid encoding MUC1-C agonist epitopes
A composition comprising the nucleic acid encoding SEQ ID NO:1 or SEQ ID NO:2 and a pharmaceutically acceptable carrier, optionally further comprising an immunostimulatory or regulatory molecule to enhance immune response.
The claims cover nucleic acids encoding the MUC1-C CTL agonist epitopes SEQ ID NO:1 or SEQ ID NO:2, vectors and cells comprising such nucleic acids, and pharmaceutical compositions containing the nucleic acids, with or without immunostimulatory/regulatory molecules, thereby protecting the use of these epitopes and their genetic sequences in therapeutic applications.
Stated Advantages
The agonist epitopes enhance the generation of T cells that recognize and lyse MUC1-expressing tumor cells more efficiently than native epitopes.
The peptides and compositions stimulate significant antigen-specific cellular immune responses, including IFN-γ production by CTLs.
The yeast-based immunotherapeutic compositions expressing MUC1 agonist epitopes effectively activate MUC1-specific T cells restricted by multiple HLA types (A2, A3, A24), thus broadening patient applicability.
The MUC1 agonist epitopes can be used therapeutically to prevent, treat, inhibit, or delay progression and metastasis of MUC1-expressing cancers.
The compositions can be administered using multiple routes and schedules, alone or in combination with other cancer therapies or immunostimulatory molecules, increasing clinical versatility.
Documented Applications
Prevention and therapy of cancers expressing or overexpressing MUC1, including breast, ovarian, lung, colon, prostate, pancreatic, gastric, head and neck, and hematologic malignancies.
Generation and activation of MUC1-specific cytotoxic T lymphocytes in vivo, ex vivo, and in adoptive T-cell therapies.
Use in vaccines, yeast-based immunotherapy compositions, or recombinant viral vector vaccines encoding MUC1 agonist epitopes to enhance immune responses against MUC1-expressing tumors.
Use in methods to reduce, arrest, reverse, or prevent metastatic progression of cancer expressing MUC1 in individuals.
Use in immunotherapy methods involving dendritic cell transduction or adoptive transfer of T cells stimulated with the agonist peptides or compositions.
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