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-11034740-B2
Publication Date
2021-06-15
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, nucleic acids encoding these polypeptides, non-yeast vectors comprising the nucleic acids, non-yeast cells, and methods of use. A particular embodiment includes a polypeptide comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3, which is a Brachyury deletion mutant with reduced or abolished DNA binding activity due to deletion of the DNA binding domain (residues 198-222).
The invention also encompasses methods for inducing an immune response to Brachyury by administering an effective amount of the polypeptide, nucleic acid, non-yeast vector, cell, or composition, wherein the immune response comprises a Brachyury-specific CD4+ T cell response. Further, methods for treating or preventing cancer by such administration, as well as methods for inhibiting the growth of cancer cells by contacting dendritic cells with the polypeptide to create antigen presenting cells and administering these to subjects, are provided.
The background describes the problem of needing effective immunotherapeutic interventions against cancer. Brachyury is a transcription factor important in mesoderm development and is overexpressed in various human cancers, including breast, lung, colon, prostate, hepatocellular carcinoma, and B-cell malignancies. There remains a need for reagents that induce effective immune responses against cancer, particularly those eliciting both CD4 and CD8 T cell responses to tumor antigens selectively expressed by malignant cells.
Claims Coverage
The claims set forth 7 main inventive features related to nucleic acids encoding the Brachyury deletion mutant polypeptide, vectors, cells, and compositions comprising them.
Nucleic acid encoding the Brachyury deletion mutant polypeptide
A nucleic acid encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 3.
Non-yeast vector comprising the nucleic acid
Vectors comprising the nucleic acid encoding the Brachyury deletion mutant polypeptide, including plasmid, poxvirus, retrovirus, adenovirus, herpes virus, polio virus, alphavirus, baculovirus, Sindbis virus, or bacterial vectors such as Listeria or Salmonella.
Inclusion of immunostimulatory/regulatory molecules in vector
The non-yeast vector further comprising a nucleic acid encoding immunostimulatory/regulatory molecules such as interleukins (IL-2, IL-4, IL-6, IL-12), interferon-γ, tumor necrosis factor-α, B7.1, ICAM-1, LFA-3, CD70, RANTES, granulocyte colony-stimulating factor, OX-40L, 4-1BBL, anti-CTLA-4, and combinations thereof.
Inclusion of tumor associated antigens in vector
The vector optionally further comprises nucleic acids encoding one or more tumor associated antigens.
Non-yeast cell comprising the nucleic acid
Non-yeast cells containing the nucleic acid encoding the Brachyury deletion mutant polypeptide, including antigen presenting cells or tumor cells.
Pharmaceutical composition comprising the nucleic acid
Compositions comprising the nucleic acid encoding the Brachyury deletion mutant polypeptide and a pharmaceutically acceptable carrier, optionally further comprising immunostimulatory molecules, chemotherapeutic drugs, antibiotics, antivirals, antifungals, cyclophosphamide, adjuvants, granulocyte monocyte colony stimulating factor, or liposomes.
The claims collectively cover nucleic acids encoding a Brachyury deletion mutant polypeptide, various non-yeast vectors and cells incorporating these nucleic acids, as well as pharmaceutical compositions comprising them with optional immunostimulatory agents and other therapeutic compounds.
Stated Advantages
The combination of Brachyury, CEA, and MUC1 vectors in a Tri-Ad5 vaccine elicits antigen-specific IFN-γ and IL-2 producing cells similarly to individual vaccines without significant antigenic competition.
The Brachyury deletion mutant polypeptide expressed by vectors induces a specific CD4+ and CD8+ T cell immune response.
The use of the Brachyury deletion mutant vector generates T cells capable of lysing human tumor cells expressing the antigens in an MHC-restricted manner.
The Tri-Ad5 vaccine regimen is as effective as single antigen vaccines in eliciting anti-tumor effects in vivo.
Documented Applications
Inducing specific immune responses against Brachyury in a subject, including inducing Brachyury-specific CD4+ and CD8+ T cells.
Treating or preventing various cancers expressing or capable of expressing Brachyury, including breast, lung, colon, prostate, hepatocellular carcinoma, B-cell origin malignancies, and radiation or chemotherapy resistant tumors.
Generating antigen presenting dendritic cells by contact with the Brachyury deletion mutant polypeptide and administering these cells to inhibit tumor cell growth.
Use as a vaccine in a heterologous prime/boost protocol administering recombinant non-yeast vectors encoding the Brachyury deletion mutant polypeptide with immunostimulatory molecules and/or other tumor-associated antigens.
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