Yeast-brachyury immunotherapeutic compositions
Inventors
Palena, Claudia • Guo, Zhimin • Apelian, David • Schlom, Jeffrey
Assignees
GlobeImmune Inc • US Department of Health and Human Services
Publication Number
US-10363294-B2
Publication Date
2019-07-30
Expiration Date
2032-03-19
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Abstract
Disclosed are yeast-based immunotherapeutic compositions comprising Brachyury antigens, and methods for the prevention and/or treatment of cancers characterized by the expression or overexpression of Brachyury.
Core Innovation
The invention pertains to yeast-based immunotherapeutic compositions comprising Brachyury antigens, specifically designed for the prevention and/or treatment of cancers characterized by expression or overexpression of Brachyury. These compositions utilize a yeast vehicle expressing one or more Brachyury antigens or immunogenic domains, eliciting specific cellular immune responses against Brachyury-expressing tumor cells.
Brachyury, a mesodermal transcription factor critical in embryonic development, is aberrantly expressed in many human tumors and is implicated in the epithelial-mesenchymal transition (EMT) process, which confers tumor cells with migratory and invasive properties and contributes to metastatic progression. Despite recognition of Brachyury as a novel cancer immunotherapy target, there exists a need for effective immunotherapeutic products to treat cancers associated with Brachyury expression.
The invention introduces yeast-Brachyury immunotherapy compositions capable of expanding Brachyury-specific T cells including CD8+ cytotoxic T lymphocytes from normal donors and cancer patients. Immunization with these compositions in vivo elicits antigen-specific cellular immune responses and inhibits growth of Brachyury-expressing tumors in mouse models. Moreover, the therapy can be used prophylactically to prevent or delay the onset of Brachyury-expressing cancers, therapeutically to reduce tumor burden and inhibit metastatic progression, and to reduce chemotherapy or radiation resistance associated with metastatic tumors.
Claims Coverage
The claims include three independent claims focusing on methods of treating cancer, immunotherapeutic compositions, and recombinant nucleic acid molecules or fusion proteins expressed by yeast. These independent claims cover inventive features related to yeast vehicle type, specific Brachyury antigens, and administration protocols.
Use of a whole, inactivated yeast as a vehicle for immunotherapy
The method or composition employs a whole, inactivated yeast to deliver the immunotherapeutic agent.
Incorporation of specific Brachyury antigens in the immunotherapeutic composition
The cancer antigen comprises Brachyury antigens consisting of SEQ ID NO:6, positions 2-435 of SEQ ID NO:6, SEQ ID NO:18, or positions 2-435 of SEQ ID NO:18.
Expression of Brachyury fusion protein by the yeast vehicle
The yeast expresses a Brachyury fusion protein comprising amino acid sequences of positions 2-435 of SEQ ID NO:6 or SEQ ID NO:18, which elicits a Brachyury-specific T cell response.
Formulation with pharmaceutically acceptable excipients for administration
The immunotherapeutic composition is formulated in excipients suitable for human injection.
Administration dosing regimens and routes
The method includes administering doses ranging from about 10 Y.U. to 100 Y.U., via subcutaneous injection, at intervals including weekly, biweekly, or monthly, and at multiple sites to form a single dose.
Combination with other cancer therapies
The immunotherapeutic composition may be administered concurrently with other cancer therapies.
The independent claims cover methods and compositions utilizing whole, inactivated yeast vehicles expressing defined Brachyury antigens or fusion proteins for treating various stages and types of cancer, including formulations, dosing regimens, and combination therapies, as well as supporting nucleic acid constructs encoding such fusion proteins.
Stated Advantages
Effectively targets Brachyury-expressing and metastatic cancers, including late-stage tumors.
Prevents, delays, arrests, or reverses metastatic progression of cancer.
Enhances cellular immune responses without requiring exogenous adjuvants or immunostimulatory agents.
Generates robust Brachyury-specific CD4+ and CD8+ T cell responses, including cytotoxic T lymphocyte activity.
Can be repeatedly administered without loss of efficacy.
Useful in individuals with precancerous lesions or at high risk for developing Brachyury-expressing cancers.
Can reduce or prevent chemotherapy and radiation resistance in cancer treatment.
Adaptable for personalized therapy, including combination with other tumor antigens and treatments.
Documented Applications
Prevention and/or treatment of cancers characterized by expression or overexpression of Brachyury, including breast, small intestine, stomach, pancreatic, kidney, bladder, uterine, ovarian, testicular, lung, colon, prostate cancers, chronic lymphocytic leukemia, Epstein-Barr virus transformed B cells, Burkitt's lymphoma, Hodgkin's lymphoma, and metastatic cancers thereof.
Use as an immunotherapy to inhibit or prevent metastatic progression and tumor invasion in cancer patients.
Therapy to reduce chemotherapy-resistance or radiation-resistance in patients undergoing such treatments.
Prophylactic administration to individuals at high risk or those with precancerous lesions to prevent or delay onset of Brachyury-expressing cancer.
Treatment or prevention of diseases and conditions associated with Epstein Barr Virus infection.
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