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-10550164-B2
Publication Date
2020-02-04
Expiration Date
2036-08-03
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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, nucleic acids encoding these polypeptides, non-yeast vectors comprising the nucleic acids, non-yeast cells containing the polypeptides or nucleic acids, and methods of use. Specifically, it provides a polypeptide with a deletion in the DNA binding domain (residues 198-222 of full-length Brachyury), exemplified by the sequence SEQ ID NO: 3. The mutant polypeptide has reduced or abolished DNA binding activity compared to native Brachyury.
The methods include administering the Brachyury deletion mutant polypeptide or nucleic acid encoded therein, non-yeast vectors, or non-yeast cells (e.g., dendritic cells) loaded with these polypeptides to induce Brachyury-specific CD4+ and optionally CD8+ T cell immune responses. These methods can treat, prevent, or inhibit the growth of cancers expressing or capable of expressing Brachyury. Compositions may include carriers, immunostimulatory molecules, or adjuvants to enhance immune responses.
Claims Coverage
The patent discloses 18 claims, with at least one independent claim directed to the Brachyury deletion mutant polypeptide and methods for inducing immune responses and compositions thereof.
Brachyury deletion mutant polypeptide
A polypeptide comprising the amino acid sequence of SEQ ID NO: 3, which comprises a deletion of the DNA binding domain (residues 198-222), resulting in reduced or abolished DNA binding activity.
Non-yeast cell comprising the polypeptide
A non-yeast cell that contains the Brachyury deletion mutant polypeptide as defined.
Composition comprising the polypeptide or non-yeast cell and a pharmaceutically acceptable carrier
A composition comprising either the Brachyury deletion mutant polypeptide or a non-yeast cell containing the polypeptide, along with a pharmaceutically acceptable carrier, optionally including immunostimulatory/regulatory molecules, adjuvants, chemotherapeutic agents, or liposomes.
Methods for inducing an immune response to Brachyury
Methods involving administering to a subject an effective amount of the Brachyury deletion mutant polypeptide, a non-yeast cell comprising the polypeptide, or compositions thereof, to induce a Brachyury specific CD4+ T cell response, optionally including a CD8+ T cell response, which can include measurement of the T cell response and administration with additional therapeutic agents such as chemotherapeutic drugs, radiation, or checkpoint inhibitors.
The independent claims cover the novel Brachyury deletion mutant polypeptide, non-yeast cells containing that polypeptide, compositions including the polypeptide or cells with pharmaceutically acceptable carriers and immunostimulatory agents, and methods for inducing specific immune responses to Brachyury for cancer treatment or prevention.
Stated Advantages
The Brachyury deletion mutant polypeptide induces an effective Brachyury-specific immune response comprising both CD4+ and CD8+ T cells.
The combination of multiple antigen-expressing vectors (Tri-Ad5) generates antigen-specific immune responses comparable to single antigen vaccines without antigenic competition.
Vaccination with the recombinant vectors elicits antigen-specific cellular and humoral immune responses capable of lysing tumor cells expressing Brachyury, CEA, and MUC1.
The compositions and methods permit treatment or prevention of diverse cancers expressing or capable of expressing Brachyury, including radiation or chemotherapy resistant cancers.
Documented Applications
Inducing Brachyury-specific CD4+ and CD8+ T cell immune responses in subjects.
Treating or preventing cancer in subjects by administering Brachyury deletion mutant polypeptides, nucleic acids, vectors, cells, or compositions thereof.
Inhibiting the growth of cancer cells by administering antigen-presenting cells loaded with Brachyury deletion mutant polypeptides to induce immune responses.
Using recombinant viral vectors (e.g., adenovirus vectors) expressing Brachyury deletion mutants combined with other tumor-associated antigens (CEA, MUC1) in vaccines.
Administering compositions alone or in combination with chemotherapy, radiation, checkpoint inhibitors, or other therapeutic agents.
Ex vivo generation of antigen-specific T cells using dendritic cells infected with the recombinant vectors for adoptive immunotherapy.
Interested in licensing this patent?