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-10035832-B2
Publication Date
2018-07-31
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 MUC1 oncoprotein (MUC1-C). These epitopes, specifically peptides comprising the amino acid sequences of SEQ ID NO: 1 or SEQ ID NO: 2, can be used as peptides, polypeptides (proteins), or incorporated into vaccines and various compositions for preventing or treating cancers that express or overexpress MUC1. The invention also includes nucleic acids encoding these peptides or polypeptides, vectors comprising such nucleic acids, cells expressing them, and related compositions, including yeast-based immunotherapeutic compositions.
The problem addressed relates to the oncogenic activity and clinical significance of MUC1-C, which is involved in tumor cell transformation, cancer progression, invasion, metastasis, and poor prognosis. Prior vaccine efforts largely focused on the MUC1-N region and VNTR, with limited success in eliciting effective CTL responses that recognize endogenously expressed epitopes on tumor cells. There is a need to identify novel specific CTL epitopes and enhancer agonist peptides of MUC1-C and to develop compositions and methods that effectively activate immune responses targeting these epitopes for cancer diagnosis and therapy.
The invention resolves this need by providing newly identified HLA-A24 restricted CTL agonist epitopes from the MUC1-C region, such as the peptides SEQ ID NO: 1 and SEQ ID NO: 2, which demonstrate improved T cell activation, recognition, and killing of tumor cells expressing MUC1. These epitopes are incorporated into peptides, polypeptides, nucleic acids, recombinant vectors, and yeast-based immunotherapeutic compositions to induce enhanced cellular immune responses. Methods for treatment or prevention of MUC1-expressing cancers by administering these compositions or by adoptive transfer of T cells activated against these agonist epitopes are also provided.
Claims Coverage
The patent includes several independent claims covering peptides, compositions, and proteins comprising the novel MUC1 agonist epitope sequences.
Peptide comprising the HLA-A24 MUC1 agonist epitope
A peptide comprising the amino acid sequence of SEQ ID NO: 1, specifically the agonist epitope from the MUC1-C subunit that enhances T-cell activation.
Peptide length limitation
The peptide comprises no more than 20 amino acid residues, focusing on an optimized size for immune recognition.
Composition containing the MUC1 agonist peptide
A composition that includes the MUC1 agonist peptide of SEQ ID NO: 1 combined with a pharmaceutically acceptable carrier suitable for administration.
Inclusion of immunostimulatory/regulatory molecule in compositions
Compositions further comprising an immunostimulatory or regulatory molecule to enhance the immune response.
MUC1 protein comprising the agonist epitope
A full or partial MUC1 protein or polypeptide comprising the amino acid sequence of SEQ ID NO: 1, including variant sequences harboring agonist substitutions to enhance immunogenicity.
The independent claims focus on the novel MUC1 agonist peptides of defined sequences, compositions containing these peptides with or without immunomodulatory components, and MUC1 proteins incorporating these agonist epitopes, thereby protecting compositions and methods for their use in cancer immunotherapy.
Stated Advantages
The agonist epitopes enhance generation and activation of MUC1-specific cytotoxic T lymphocytes that can effectively lyse human tumor cells expressing MUC1.
Use of the agonist peptides in vaccines or in adoptive T cell therapies provides improved immune responses compared to native epitopes.
Yeast-based immunotherapeutic compositions expressing MUC1 agonist epitopes can activate both CD4+ and CD8+ T cell responses, including in multiple HLA contexts (A2, A3, A24).
Use of neutral pH culturing improves yeast cell wall pliability and antigen accessibility, promoting beneficial immune responses.
Documented Applications
Prevention and therapeutic treatment of human cancers expressing or overexpressing MUC1, including breast, lung, ovarian, prostate, colon, pancreatic, and hematologic cancers.
Use as peptide-based vaccines, nucleic acid or vector-based vaccines, yeast-based immunotherapeutic compositions, and adoptive transfer of MUC1-specific cytotoxic T lymphocytes.
Enhancing host immune responses against MUC1-expressing tumors for reducing tumor burden, inhibiting tumor growth, preventing metastatic progression, and improving survival.
Ex vivo stimulation of dendritic cells or peripheral blood mononuclear cells with compositions containing the agonist epitopes for therapeutic administration.
Use in prime-boost vaccination protocols employing recombinant viral vectors expressing MUC1 agonist epitopes to induce cellular immunity.
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