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-11155588-B2
Publication Date
2021-10-26
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), including peptides with the amino acid sequences of SEQ ID NO: 1 or SEQ ID NO: 2. These peptides, polypeptides (proteins), nucleic acids encoding them, vectors comprising such nucleic acids, cells expressing them, and compositions thereof can be used in vaccines or other immunotherapeutic compositions for the prevention or therapy of cancers expressing or overexpressing MUC1.
MUC1 is a type I membrane glycoprotein composed of a large N-terminal subunit (MUC1-N) and a small C-terminal subunit (MUC1-C). The MUC1-C region contains distinct domains, including a small extracellular domain, a transmembrane domain, and a cytoplasmic tail involved in signaling and oncogenic transformation. MUC1-C interactions promote cancer cell growth, motility, invasion, metastasis, and drug resistance. Current MUC1 vaccine trials have largely targeted the VNTR region of MUC1-N but have limited success in eliciting effective tumor killing.
The problem solved by the invention is the identification and development of new specific CTL epitopes and enhancer agonist peptides within the MUC1-C region that effectively stimulate T-cell activation leading to tumor cell lysis. The invention addresses the need for improved compositions and methods using these epitopes for the diagnosis and treatment of MUC1-expressing cancers. It also provides immunotherapeutic compositions, including yeast-based vaccines, which express modified MUC1 antigens incorporating these agonist epitopes to enhance immune responses against tumors.
Claims Coverage
The patent contains one independent claim directed to a yeast-based MUC1 immunotherapeutic composition. The claim describes the main inventive features of the composition involving a yeast vehicle and a fusion protein with specific amino acid substitutions in MUC1 antigen.
Yeast-based MUC1 immunotherapeutic composition comprising a modified MUC1 antigen
The composition comprises a whole-inactivated yeast expressing a fusion protein that includes a MUC1 antigen with amino acid substitutions at sequence positions T93, A141, P142, G149, I150, T151, A392, C406, T422, P430, T431, T444, D445, and S460 relative to the wild-type MUC1 sequence (SEQ ID NO:14).
Specific amino acid substitutions in the MUC1 antigen
The MUC1 antigen specifically includes substitutions at T422K, P430A, T431L, T444L, D445F, and S460Y positions relative to wild-type MUC1.
Heat-inactivated Saccharomyces cerevisiae yeast vehicle
The yeast used in the immunotherapeutic composition is whole-inactivated (heat-killed) and from the species Saccharomyces cerevisiae.
Production of composition under controlled pH conditions
The yeast-based immunotherapeutic composition is produced by culturing whole yeast expressing the MUC1 antigen in a medium maintained at a pH level between 5.5 and 8.
The claims cover a yeast-based immunotherapeutic composition comprising heat-inactivated Saccharomyces cerevisiae yeast expressing a fusion protein with a modified MUC1 antigen containing specific amino acid substitutions enhancing immunogenicity, produced under neutral to mildly acidic pH conditions to optimize antigen presentation and immune activation.
Stated Advantages
Enhanced generation of cytotoxic T lymphocytes that efficiently lyse human tumor cells expressing native MUC1.
Capability to stimulate MUC1-specific CD8+ and CD4+ T cell-mediated immune responses, including against multiple HLA types (A2, A3, A24).
The yeast-based immunotherapeutic composition cultured under neutral pH conditions produces yeast with flexible cell walls, enhancing immune responses via increased cytokine secretion by antigen-presenting cells and improved antigen accessibility.
Compositions comprising MUC1-C agonist epitopes provide improved treatment efficacy for MUC1-expressing cancers, including prevention, inhibition, and delay of tumor progression and metastasis.
Documented Applications
Preventing or delaying the onset of MUC1-expressing cancers in individuals at risk.
Therapeutic treatment of MUC1-expressing cancers, including reducing tumor burden, inhibiting tumor growth, and improving survival.
Inhibiting metastatic progression and tumor invasion in individuals with MUC1-expressing cancers.
Use as vaccines or immunotherapeutic compositions employing peptides, polypeptides, nucleic acids, viral vectors, cells (including dendritic cells), or yeast-based immunotherapy compositions to elicit immune responses against MUC1-expressing tumors.
Activation of T cells ex vivo or in vivo for adoptive transfer therapies targeting MUC1-expressing cancers.
Use of yeast-MUC1 immunotherapeutic compositions (such as GI-6108) to activate MUC1-specific T cells via dendritic cell presentation.
Administration of yeast-MUC1 immunotherapy in clinical trial settings to treat patients with MUC1-positive tumors and various HLA types by subcutaneous injections at escalating doses.
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