Yeast-MUC1 immunotherapeutic compositions and uses thereof
Inventors
Franzusoff, Alex • Guo, Zhimin • Schlom, Jeffrey • Tsang, Kwong-Yok
Assignees
GlobeImmune Inc • US Department of Health and Human Services
Publication Number
US-9533031-B2
Publication Date
2017-01-03
Expiration Date
2032-08-17
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Abstract
Disclosed are yeast-based immunotherapeutic compositions comprising mucin-1 (MUC1), as well as methods for the prevention and/or treatment of cancers characterized by the expression or overexpression of mucin-1 (MUC1).
Core Innovation
The invention relates to yeast-based immunotherapeutic compositions comprising mucin-1 (MUC1) antigens, and methods for the prevention and/or treatment of cancers characterized by the expression or overexpression of MUC1. These yeast-MUC1 immunotherapy compositions include a yeast vehicle and at least one MUC1 antigen, often expressed as a fusion protein by the yeast vehicle. The yeast vehicle can be intact yeast, killed yeast, yeast derivatives such as spheroplasts or ghosts, or yeast membrane particles.
The problem being addressed is that many human cancers overexpress MUC1, and current therapies targeting the MUC1-N subunit have not been successful clinically, possibly due to shedding of the MUC1-N portion. MUC1-C is considered an oncoprotein involved in tumor progression, and there are no approved cancer therapies specifically targeting MUC1. Thus, there remains a need for new products that effectively treat or prevent MUC1-associated cancers.
The invention provides yeast-MUC1 immunotherapeutic compositions that elicit MUC1-specific cellular immune responses without the need for exogenous adjuvants, cytokines, or immunostimulatory molecules. These compositions are capable of activating both CD4+ and CD8+ T cells, inducing TH1 and TH17 responses, and reducing regulatory T cell function to enhance anti-tumor immunity. The yeast vehicle can be manipulated to express various MUC1 antigen domains in fusion proteins, including SEA/extracellular domain, variable number of tandem repeats (VNTR), transmembrane, and cytoplasmic domains. The compositions can be adapted to different cancer types, stages, and patient statuses, and may be combined with other immunotherapeutics or conventional therapies.
Claims Coverage
The claimed invention is covered by one independent claim describing a yeast-MUC1 immunotherapeutic composition. The main inventive features focus on the composition comprising a yeast vehicle expressing a MUC1 antigen with specific amino acid substitutions.
Yeast-based immunotherapeutic composition comprising MUC1 agonist antigen
The composition comprises a yeast vehicle and at least one MUC1 antigen expressed by the yeast vehicle, wherein the MUC1 antigen comprises an amino acid sequence at least 95% identical to SEQ ID NO:25 or positions 92-566 of SEQ ID NO:25, with 2 to 11 specific amino acid substitutions selected from L184, Y232, L233, V240, Y241, L242, Y483, V497, L535, F536 and Y551, creating a MUC1 agonist antigen that enhances immunogenicity.
Yeast vehicle characteristics
The yeast vehicle can be whole yeast (heat-inactivated), and is preferably from a mutant yeast strain that produces underglycosylated proteins compared to wild-type strains, such as Saccharomyces cerevisiae, which influences antigen expression and immune responses.
The claims primarily protect yeast-MUC1 immunotherapeutic compositions comprising yeast vehicles expressing MUC1 agonist antigens having specific amino acid substitutions enhancing immunogenicity, and specify yeast strain and inactivation features. The invention covers both the antigen sequence and the yeast vehicle characteristics critical for inducing effective immune responses.
Stated Advantages
Yeast-MUC1 immunotherapy elicits broad cellular immune responses including CD4+ and CD8+ T cell activation without exogenous adjuvants or immunostimulatory agents.
The compositions mature dendritic cells and increase cytokine production associated with effective anti-tumor immunity.
Yeast-MUC1 immunotherapy inhibits regulatory T cell numbers/functionality, enhancing effector T cell responses against tumors.
The yeast platform allows personalized adaptation to different cancer types, stages, and patient conditions, and can be combined with other immunotherapeutics and therapies.
Recombinant fusion proteins with multiple MUC1 domains enhance immune recognition and eliminate the need to identify specific epitopes.
Production of yeast at neutral pH improves immunogenicity and dendritic cell activation without reducing antigen expression levels.
Documented Applications
Use of yeast-MUC1 immunotherapeutic compositions for prevention and/or treatment of cancers expressing or overexpressing MUC1, including epithelial cancers such as breast, colon, pancreas, ovarian, esophageal cancers, and hematologic cancers like acute myeloid leukemia (AML).
Yeast-MUC1 immunotherapy applied prophylactically in individuals with premalignant lesions or at high risk for MUC1-expressing cancers to prevent or delay cancer onset.
Therapeutic use in individuals with detected MUC1-expressing cancers to reduce tumor burden, inhibit tumor growth, arrest cancer progression, and increase survival.
Use in combination with other therapies such as chemotherapy, radiation, surgical resection, targeted therapies, adoptive T cell transfer, viral vector vaccines, dendritic cell/tumor fusion therapies, and other immunotherapies targeting MUC1 or different tumor antigens.
Administration in clinical trial settings for AML patients as an add-on to standard chemotherapy, and for bone marrow transplantation recipients and donors to prevent relapse.
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