Brachyury deletion mutants, non-yeast vectors encoding brachyury deletion mutants, and their use
Inventors
Schlom, Jeffrey • Palena, Claudia M.
Assignees
US Department of Health and Human Services
Publication Number
US-12012438-B2
Publication Date
2024-06-18
Expiration Date
2036-08-03
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Abstract
The invention provides Brachyury deletion mutant polypeptides, nucleic acids encoding the polypeptides, non-yeast vectors comprising the nucleic acids, non-yeast cells, and methods of use.
Core Innovation
The invention provides Brachyury deletion mutant polypeptides and nucleic acids encoding these polypeptides, as well as non-yeast vectors comprising these nucleic acids, non-yeast cells, and compositions thereof. The mutant polypeptides include a specific Brachyury deletion mutant comprising the amino acid sequence of SEQ ID NO: 3. The invention also offers methods of use including inducing an immune response specific to Brachyury by administering an effective amount of the polypeptide, nucleic acid, non-yeast vector, cell, or composition, wherein the immune response includes a Brachyury specific CD4+ T cell response.
The invention addresses the need for reagents that induce an effective immune response to cancer, including both CD4 and CD8 T cell responses. The Brachyury gene, important in mesoderm development, is overexpressed in various human carcinomas and malignancies such as breast, lung, colon, prostate, hepatocellular carcinoma, and B-cell origin cancers. Immunotherapeutic interventions target molecules selectively expressed by malignant cells that are also essential for tumor progression. Accordingly, the mutant Brachyury polypeptides are developed to reduce or abolish DNA binding activity of Brachyury, facilitating their use in inducing immune responses against Brachyury-expressing cancer cells.
Claims Coverage
The patent includes one independent claim focusing on a Tri-adenovirus serotype 5 (Tri-Ad5) vaccine composition and a corresponding method for treating tumors expressing CEA, Brachyury, or MUC1.
Tri-Ad5 vaccine composition with Brachyury deletion mutant
A vaccine composition comprising equal parts of three modified Ad5 [E1-, E2b-] vectors respectively encoding Brachyury (with the sequence of SEQ ID NO: 3), carcinoembryonic antigen (CEA), and mucin 1 (MUC1). The Ad5 vector is modified by removal of early 1 (E1) and early 2b (E2b) gene regions.
Formulation and additional components of the vaccine composition
The vaccine composition can further include immunostimulants such as an IL-15/IL-15 receptor complex, chemotherapeutic drugs, antibiotics, antivirals, antifungals, cyclophosphamide, or combinations thereof, and is formulated for subcutaneous injection.
Method of treating tumors using the Tri-Ad5 composition
A method of treating tumors expressing at least one of CEA, Brachyury, or MUC1 by administering the Tri-Ad5 vaccine composition to a subject, including specific administration doses ranging from 1×10^5 to 1×10^12 viral particles per vector, and optionally administering immunostimulants or therapeutic agents. The tumors include those of the small intestine, stomach, kidney bladder, uterus, ovary, testes, lung, colon, prostate, bronchial tube, chronic lymphocytic leukemia, B cell-based malignancies, and breast cancers such as infiltrating ductal carcinoma or estrogen receptor negative and progesterone negative breast cancer.
Administration protocols
The vaccine composition is administered subcutaneously, potentially in prime and boost regimens with boosts given every two, four, or six weeks, to human subjects in need of treatment.
The claims cover the Tri-Ad5 vaccine composition comprising the Brachyury deletion mutant and two other tumor antigens, its formulation with immunostimulants and drugs, and methods for treating various cancers expressing the relevant antigens using specific dosing and administration schedules.
Stated Advantages
The Tri-Ad5 vaccine induces antigen-specific IFN-γ- and IL-2-producing T cell responses similar to single antigen vaccines without significant antigenic competition.
The vaccine elicits multifunctional CD4+ and CD8+ T cells that produce cytokines such as IFN-γ and TNF-α.
The vaccine generates humoral responses including antibodies capable of complement-dependent cytotoxicity against tumor cells expressing CEA.
The Tri-Ad5 vaccine is as effective as single-vector vaccines in inhibiting tumor growth in vivo.
Documented Applications
Inducing Brachyury-specific CD4+ and CD8+ T cell immune responses for cancer immunotherapy.
Treatment or prevention of cancers expressing Brachyury, CEA, and/or MUC1, including breast cancer, colon cancer, pancreatic cancer, and other carcinomas or malignancies.
Generating antigen-specific cytotoxic T lymphocytes capable of lysing tumor cells endogenously expressing these antigens.
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