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-11732017-B2
Publication Date
2023-08-22
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) oncoprotein, particularly peptides comprising the amino acid sequences of SEQ ID NO: 1 or SEQ ID NO: 2. These peptides, polypeptides, or proteins can be used in vaccines or other compositions for the prevention or therapy of cancer. The invention also provides nucleic acids encoding these peptides or proteins, vectors comprising these nucleic acids, cells expressing the peptides or nucleic acids, and compositions thereof, including yeast-MUC1 immunotherapeutic compositions comprising a yeast vehicle and a fusion protein with at least one MUC1 antigen containing said epitopes.
MUC1 is a type I membrane glycoprotein composed of a large extracellular N-terminal subunit (MUC1-N) and a small C-terminal subunit (MUC1-C). The MUC1-C region contains a small extracellular domain, a transmembrane domain, and a cytoplasmic tail involved in oncogenic signaling through interactions with proteins like β-catenin and EGFR. Such interactions are significant in tumor cells due to loss of polarity, contributing to transformation, increased growth, invasion, metastasis, and drug resistance in various cancers.
Existing vaccine efforts focused mainly on MUC1-N tandem repeats have shown limited success. There is a need to identify new CTL epitopes and enhancer agonist peptides in MUC1-C that improve T cell activation and killing of tumor cells. The invention addresses this by providing MUC1-C agonist epitopes with specific amino acid substitutions that enhance T cell responses and enable recognition of native epitopes on MUC1-expressing tumor cells, thereby potentially improving cancer immunotherapy outcomes.
Claims Coverage
The patent contains one independent claim concerning a yeast-MUC1 immunotherapeutic composition with specific inventive features related to antigen amino acid substitutions and yeast expression.
Composition comprising yeast vehicle and fusion protein with MUC1 antigen substitutions
The composition includes a yeast vehicle and a fusion protein with at least one MUC1 antigen. The MUC1 antigen differs from a wild-type MUC1 protein (SEQ ID NO:14) by at least one amino acid substitution at specific positions selected from T93, A141, P142, G149, S150, and T151. The fusion protein is expressed by the yeast vehicle.
Use of whole or heat-inactivated yeast vehicle
The yeast vehicle can be whole yeast or heat-inactivated yeast.
Yeast from Saccharomyces cerevisiae species
The yeast vehicle is specifically from the species Saccharomyces cerevisiae.
Specific amino acid substitutions in MUC1 antigen
The MUC1 antigen comprises at least one amino acid substitution selected from the group consisting of T93L, A141Y, P142L, G149V, S150Y, and T151L, referring to positions in the wild-type SEQ ID NO:14.
Production of composition under controlled pH conditions
The immunotherapeutic composition is produced by culturing the whole yeast expressing the MUC1 antigen in a medium maintained at a pH between 5.5 and 8.
The claims protect a yeast-based immunotherapeutic composition expressing a fusion protein with specific MUC1 antigen amino acid substitutions, particularly in positions associated with enhancer agonist epitopes, produced using Saccharomyces cerevisiae yeast. The claims cover forms of the yeast vehicle, defined antigen substitutions, and production conditions influencing antigen expression.
Stated Advantages
The agonist epitopes enhance generation of T cells that efficiently lyse human tumor cells expressing native MUC1 epitopes.
The yeast-MUC1 immunotherapeutic compositions stimulate MUC1-specific cellular immune responses, including CD4+ and CD8+ T cell responses, against MUC1-expressing cancers.
The use of yeast vehicles cultured under controlled pH results in yeast with pliable cell walls that promote superior immune responses by antigen presenting cells.
Inclusion of multiple HLA-restricted agonist epitopes (e.g., HLA-A2, A3, and A24) in the MUC1 antigen enhances applicability across a variety of individual HLA types.
Documented Applications
Use of peptides, polypeptides, nucleic acids, vectors, cells, or yeast-MUC1 immunotherapeutic compositions to enhance immune responses against MUC1-expressing cancers in subjects.
Therapeutic use in treatment of MUC1-expressing cancers, including preventing, arresting, reversing, or reducing metastatic progression and tumor growth.
Prophylactic use to prevent or delay onset of MUC1-expressing cancers in at-risk individuals.
Ex vivo stimulation of lymphocytes or dendritic cells with the peptides or compositions to generate cytotoxic T lymphocytes for adoptive cell therapy.
Administration of yeast-MUC1 immunotherapeutic compositions, including via various routes (e.g., subcutaneous, intravenous), alone or with adjuvants or immunostimulatory molecules like GM-CSF, for cancer immunotherapy.
Use in prime and boost vaccination protocols with recombinant viral vectors encoding MUC1 antigens for improved immunogenicity.
Clinical evaluation in dose-escalation trials for safety and immunogenicity in subjects with MUC1-positive tumors.
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