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-10188714-B2
Publication Date
2019-01-29
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 provides yeast-based immunotherapeutic compositions comprising mucin-1 (MUC1), specifically yeast-MUC1 immunotherapeutic compositions including a yeast vehicle and a fusion protein expressed by the yeast vehicle that comprises at least one MUC1 antigen. These compositions and methods are intended for the prevention and/or treatment of cancers characterized by the expression or overexpression of MUC1.
The MUC1 antigen in the fusion protein can include domains such as the SEA/extracellular domain (ED), variable number tandem repeat (VNTR) domains, transmembrane (TM) domain, and cytoplasmic domain (CD). Variants including at least two VNTR domains or multiple CD domains are described, with specific sequences identified by SEQ ID numbers and percentages of sequence identity. Additionally, MUC1 agonist antigens containing between one and eleven amino acid substitutions to form agonist epitopes are also encompassed.
The background describes the problem that many human carcinomas and hematologic malignancies exhibit aberrant overexpression of MUC1, which contributes to cancer progression and immune evasion. Prior approaches targeting MUC1, especially the MUC1-N subunit, have not been clinically successful, and there are no approved therapies that specifically target MUC1. Therefore, there is a need for novel compositions that effectively treat or prevent MUC1-expressing cancers.
Claims Coverage
The patent includes one independent claim detailing a method for treating MUC1-expressing cancers by administering a yeast-based immunotherapeutic composition expressing a MUC1 antigen with specific amino acid substitutions. Key inventive features are identified below.
Use of a yeast vehicle expressing a modified MUC1 antigen
The method involves administering an immunotherapeutic composition comprising a yeast vehicle expressing a MUC1 antigen having an amino acid sequence at least 95% identical to SEQ ID NO:25 or positions 92-566 of SEQ ID NO:25, incorporating between 2 and 11 specific amino acid substitutions (L184, Y232, L233, V240, Y241, L242, Y483, V497, L535, F536, and Y551).
Treatment of MUC1-expressing cancers at various stages
The method is applicable to individuals whose cancer expresses MUC1, including those with stage I, II, III or IV cancer.
Combination with other cancer therapies
The method contemplates administration alongside other cancer therapies like chemotherapy, targeted therapy, radiation, adoptive T cell transfer, or administration of additional immunotherapeutic compositions targeting either MUC1 or other cancer antigens (e.g., mutated Ras, CEA, Brachyury, and others). Additional combinations include viral vector vaccines and dendritic cell/tumor cell fusion immunotherapy.
Use in epithelial and hematologic cancers
The method applies broadly to epithelial cancers and hematological malignancies such as breast cancer, colon cancer, AML, CLL, melanoma, lymphoma, and others, including metastatic cancers. Specifically, it includes administration to both donors and recipients in bone marrow transplantation and in conjunction with cytarabine and anthracycline therapy for AML treatment.
The claims collectively cover the method of treating or managing MUC1-expressing cancers using yeast-based immunotherapeutic compositions expressing MUC1 antigens with specific agonist substitutions, across multiple cancer types and stages, optionally in combination with other therapeutic modalities.
Stated Advantages
Yeast-MUC1 immunotherapy compositions elicit MUC1-specific cellular immune responses, including CD4+ and CD8+ T cell activation, without requiring exogenous adjuvants, cytokines, or other immunostimulatory molecules.
These compositions inhibit regulatory T cell (Treg) functionality or numbers, enhancing effector T cell responses otherwise suppressed by tumors.
Yeast-MUC1 immunotherapy effectively activates antigen presenting cells and uniquely cross-primes immune responses to generate CD8+ cytotoxic T lymphocyte responses effective against tumors.
The use of longer polypeptides and fusion proteins enables targeting of multiple CD4+ and CD8+ T cell epitopes, eliminating the need for identification of precise epitopes.
Immunotherapeutic compositions can be administered repeatedly without diminishing efficacy.
Culturing yeast under neutral pH conditions produces yeast vehicles with enhanced dendritic cell activation and cytokine production, resulting in more potent immune responses.
Documented Applications
Prevention and/or treatment of cancers characterized by expression or overexpression of MUC1.
Use in prophylactic vaccination in individuals at high risk for MUC1-positive cancers or with pre-cancerous lesions.
Therapeutic administration for individuals with diagnosed MUC1-expressing cancers at stages I through IV.
Use as a combination therapy with chemotherapy, radiation, targeted therapy, adoptive T cell transfer, bone marrow transplantation, viral vector vaccines, dendritic cell/tumor fusion immunotherapy, or other immunotherapies.
Treatment of a wide range of epithelial cancers (e.g., breast, colon, pancreas, ovarian, esophageal) and hematological cancers (e.g., AML, CLL, multiple myeloma, lymphomas).
Prevention or delay of metastatic progression of MUC1-expressing cancers.
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