Brachyury polypeptides and methods for use
Inventors
Schlom, Jeffrey • Palena, Claudia M. • Kozlov, Andrei P. • Tsang, Kwong-Yok
Assignees
US Department of Health and Human Services
Publication Number
US-8613933-B2
Publication Date
2013-12-24
Expiration Date
2028-02-27
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Abstract
It is disclosed herein that Brachyury is expressed in human tumors, specifically in tumors of the small intestine, stomach, kidney, bladder, uterus, ovary, and testes, as well as in lung, colon and prostate carcinomas. Immunogenic Brachyury polypeptides are disclosed herein. These polypeptides can be used in diagnostic assays for Brachyury expression, as well as for inducing an immune response to Brachyury. Polynucleotides encoding the immunogenic Brachyury polypeptides, vectors including these polypeptides, host cells transformed with these vectors, and methods of using these polypeptides, polynucleotides, vectors, and host cells are provided. Methods of diagnosing a Brachyury-expressing cancer are also provided. Exemplary cancers include small lung, colon, intestine, stomach, kidney, bladder, uterus, ovary, and testes and prostate cancers. Methods of treating cancer are also disclosed.
Core Innovation
The invention disclosed concerns Brachyury polypeptides that are expressed in human tumors of various types, including those of the small intestine, stomach, kidney, bladder, uterus, ovary, testes, lung, colon, and prostate carcinomas, as well as chronic lymphocytic leukemia and other B cell-based malignancies. The invention provides immunogenic Brachyury polypeptides, polynucleotides encoding these polypeptides, vectors including these polynucleotides, and host cells transformed with these vectors. Methods for inducing an immune response to Brachyury, for diagnosing a Brachyury-expressing cancer, and for treating cancer with these compositions are disclosed.
The background emphasizes that while Brachyury has been known as a marker for mesodermal differentiation and expressed in embryonic and certain tumor tissues, there is a need for additional antigens to aid in the diagnosis and immunotherapy of cancers of different organs. The invention addresses this need by identifying Brachyury expression in human tumors and providing immunogenic peptides useful in diagnostic assays and therapeutic methods, including inducing cytotoxic T lymphocyte responses to Brachyury-expressing tumor cells.
Claims Coverage
The patent includes 29 claims focusing on methods of eliciting immune responses against cancer cells expressing Brachyury, as well as methods of treating such cancers using poxviral vectors encoding Brachyury polypeptides and costimulatory molecules. The claims disclose both single recombinant viruses and compositions of multiple recombinant viruses for co-expression.
Method of eliciting an immune response using a poxviral vector encoding Brachyury and costimulatory molecules
Administering a therapeutically effective amount of a composition comprising a poxviral vector encoding at least one costimulatory molecule and encoding a Brachyury polypeptide with at least 95% sequence identity to SEQ ID NO: 1 to a subject having selected cancers, thereby producing an immune response to cells expressing the Brachyury polypeptide.
Encoding of specific costimulatory molecules in the poxviral vector
The poxviral vector encodes costimulatory molecules including but not limited to B7-1, LFA-3, and ICAM-1 to enhance immune response.
Use of additional immunomodulatory agents
The method can include administering agents such as IL-2, CD72, GM-CSF, TNF-α, IFN-γ, IL-12, IL-6, or their encoding nucleic acids, in combination to augment the immune response.
Selection of poxviral vector types
The poxviral vector can be from orthopox, avipox, fowlpox, capripox, suipox, or vaccinia virus genera, including modified vaccinia virus Ankara (MVA).
Repeated administration with different poxviruses
Additional therapeutically effective doses may be administered, with poxviruses of different genus used for boosting, such as an avipox virus (fowlpox) after initial immunization.
Use of compositions comprising two recombinant poxviruses
Administration of a composition comprising a first recombinant poxvirus encoding a Brachyury polypeptide at least 95% identical to SEQ ID NO:1, and a second recombinant poxvirus encoding at least one costimulatory molecule, co-infecting host cells to coexpress both, for eliciting an immune response in a subject having specified cancers.
Methods of treating cancer by administering such vectors or compositions
Selecting subjects with cancers expressing a Brachyury polypeptide at least 95% identical to SEQ ID NO:1 and administering therapeutically effective amounts of the poxviral vector encoding Brachyury and costimulatory molecules or the dual recombinant virus compositions to treat the subject by decreasing cancer growth.
The claims cover methods of generating immune responses and treating various human cancers by administering recombinant poxviral vectors or compositions encoding immunogenic Brachyury polypeptides alongside costimulatory molecules, including dosage regimens and vector types, demonstrating inventive features related to cancer immunotherapy targeting Brachyury-expressing tumors.
Stated Advantages
Provides immunogenic Brachyury polypeptides useful for inducing immune responses against cancer cells expressing Brachyury.
Allows for diagnostic assays to detect Brachyury expression in tumors, aiding cancer diagnosis and tumor origin determination.
Enables treatment methods that include the induction of specific cytotoxic T lymphocytes targeting Brachyury-expressing tumor cells.
The use of poxviral vectors expressing both Brachyury and costimulatory molecules enhances immune response effectiveness.
Methods can be combined with other biological adjuvants, cytokines, and chemotherapeutic agents to improve therapeutic outcomes.
Documented Applications
Diagnostic assays for Brachyury expression in tumors of the small intestine, stomach, kidney, bladder, uterus, ovary, testes, lung, colon, prostate, and B cell malignancies such as CLL and lymphomas.
Inducing immune responses, specifically cytotoxic T lymphocyte responses, against Brachyury-expressing tumor cells to target cancers.
Therapeutic treatment of subjects with cancers expressing Brachyury polypeptides, including vaccines using recombinant poxviral vectors encoding Brachyury and costimulatory molecules.
Use of inhibitory nucleic acids such as siRNAs or antisense molecules targeting Brachyury mRNA to reduce tumor growth or metastasis in cancers expressing Brachyury.
Producing antigen-presenting cells pulsed with Brachyury peptides for adoptive immunotherapy in cancer patients.
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