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-11065318-B2
Publication Date
2021-07-20
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. It involves the construction and production of novel yeast-MUC1 immunotherapy products, which mature human dendritic cells, increase cytokine production associated with beneficial immune responses, and elicit activation of MUC1-specific T cell lines, leading to MUC1-specific cellular immune responses (CD4+ and CD8+).
MUC1 is a large glycoprotein expressed normally at basal levels on epithelial secretory tissues and is aberrantly overexpressed in various cancers. It exists as a heterodimer of MUC1-N and MUC1-C subunits. MUC1 overexpression is linked to tumorigenic processes, immune evasion, and metastatic spread. The MUC1-C subunit is considered an oncoprotein involved in diverse signaling pathways linked to tumorigenesis. Existing therapeutic approaches targeting MUC1-N have not been successful, possibly due to interference from shed MUC1-N, and no approved MUC1-targeted therapies exist.
The invention solves the need for effective therapies by developing yeast-MUC1 immunotherapeutic compositions where yeast vehicles express fusion proteins comprising specific portions of MUC1, including SEA/extracellular domains, variable number of tandem repeat (VNTR) domains, transmembrane and cytoplasmic domains. These compositions induce potent cellular immune responses without exogenous adjuvants or immunostimulatory molecules, decreasing regulatory T cell function and effectively activating antigen presenting cells and CD8+ cytotoxic T lymphocytes against MUC1-expressing tumors. The yeast-MUC1 immunotherapy is adaptable to different cancers, cancer stages, and individual medical statuses for broad prophylactic and therapeutic applications.
Claims Coverage
The claims include one independent claim covering a combination immunotherapeutic composition comprising a yeast-MUC1 immunotherapeutic composition and a virus-based immunotherapeutic composition. Main inventive features are detailed below.
Yeast-MUC1 immunotherapeutic composition comprising a fusion protein with a MUC1 agonist antigen
The composition includes a yeast vehicle expressing a fusion protein that comprises a MUC1 antigen with at least 95% amino acid identity to SEQ ID NO:25 and includes at least two amino acid substitutions selected from L184, Y232, L233, V240, Y241, L242, Y483, V497, L535, F536, and Y551 relative to SEQ ID NO:25.
Inclusion of a virus-based immunotherapeutic composition with a recombinant viral vector encoding a cancer antigen
The combination includes a virus-based immunotherapeutic composition comprising a recombinant viral vector encoding a cancer antigen, optionally including vectors encoding immunomodulatory compounds.
Yeast vehicle characteristics
The yeast vehicle is specified as whole yeast, heat-inactivated yeast, or from Saccharomyces cerevisiae species.
Optional inclusion of immunomodulatory compounds
The combination immunotherapeutic composition may further comprise immunomodulatory compounds such as cytokines, chemokines, antibodies, small molecules, and others, which may be encoded in the same or different viral vectors within the virus-based immunotherapy.
The claims cover a combination immunotherapeutic composition comprising a yeast vehicle expressing a specified MUC1 agonist antigen fusion protein with particular amino acid substitutions and a virus-based immunotherapeutic composition encoding a cancer antigen, optionally including immunomodulatory compounds. The yeast vehicle features and optional composition elements provide a multifaceted cancer immunotherapy approach.
Stated Advantages
Yeast-MUC1 immunotherapy compositions elicit potent cellular immune responses against MUC1 expressing tumors without the need for exogenous adjuvants, cytokines, or immunostimulatory molecules, reducing associated toxicity.
They promote maturation of dendritic cells and increase production of cytokines that enhance TH1 and CD8+ T cell responses, including IFN-γ.
They inhibit regulatory T cell numbers or functionality, enhancing effector T cell responses.
The compositions enable induction of multiple CD4+ and CD8+ T cell epitopes without prior knowledge of specific epitope structures, eliminating the need for complex algorithms and improving therapeutic flexibility.
The yeast vehicles can be cultured under neutral pH conditions to produce more immunogenic yeast with pliable cell walls, improving antigen accessibility and cytokine induction.
Yeast-MUC1 immunotherapy can be administered repeatedly without loss of efficacy.
Documented Applications
The yeast-MUC1 immunotherapeutic compositions and methods are explicitly described for the prevention and/or treatment of cancers characterized by MUC1 expression or overexpression, including use in individuals with stage I-IV cancers or pre-cancerous conditions.
Use of yeast-MUC1 immunotherapy to reduce tumor burden, inhibit tumor growth, increase survival, prevent or delay metastatic progression of cancer, and prevent or delay onset of MUC1-expressing cancers.
Combination use of yeast-MUC1 immunotherapy with other immunotherapeutic compositions targeting different tumor antigens or with other cancer therapies including chemotherapy, radiation, adoptive T cell transfer, surgical resection, and stem cell transplantation.
Clinical trial applications in subjects with MUC1-positive cancers, including an open-label phase 1 dose-escalation trial monitoring safety, immune response, and clinical activity.
Treatment of acute myeloid leukemia (AML) expressing MUC1 with yeast-MUC1 immunotherapy in combination with standard chemotherapy and bone marrow transplantation (BMT) to prevent relapse and enhance outcomes.
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