Immunogenic peptides and methods of use
Inventors
Schlom, Jeffrey • Tsang, Kwong-Yok • Pastan, Ira H.
Assignees
US Department of Health and Human Services
Publication Number
US-9175057-B2
Publication Date
2015-11-03
Expiration Date
2027-02-21
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Abstract
The PAGE4 gene is expressed in reproductive tissues, and is expressed in reproductive cancers, such as prostate cancer, uterine cancer, and testicular cancer. Immunogenic PAGE4 polypeptides are disclosed herein, as are nucleic acids encoding the immunogenic PAGE4 polypeptides, vectors including these polynucleotides, and host cells transformed with these vectors. These polypeptides, polynucleotides, vectors, and host cells can be used to induce an immune response to PAGE4. Diagnostic methods to detect PAGE4 are also described.
Core Innovation
The invention relates to immunogenic PAGE4 polypeptides derived from the PAGE4 gene, which is expressed in reproductive tissues and reproductive cancers, including prostate, uterine, cervical, and testicular cancer. The invention provides isolated immunogenic PAGE4 polypeptides comprising specific amino acid sequences of the PAGE4 protein, as well as nucleic acids encoding these polypeptides, vectors containing these nucleic acids, and host cells transformed with these vectors. These components are used to induce an immune response against PAGE4, with applications in diagnosis and treatment of PAGE4-expressing cancers.
The problem addressed by the invention stems from the high incidence and mortality of prostate cancer and other reproductive cancers, as well as limitations of current treatments such as surgery, radiation, and chemotherapy. Early detection is challenging due to false positives in screening, and treatments have limited efficacy, especially in metastatic cases. Alternative therapeutic strategies, notably immunotherapy, are desired to improve outcomes by enhancing the immune response, particularly the cytotoxic T lymphocyte response against tumor-specific antigens.
The invention recognizes the potential of immunotherapy based on cell-mediated immunity using tumor-associated antigens presented within MHC Class I molecules to CD8+ cytotoxic T lymphocytes. The PAGE4 gene, expressed in cancerous reproductive tissues, provides novel antigenic peptides for developing immunogenic compositions and diagnostic methods. The disclosed immunogenic peptides include specific short polypeptides of PAGE4 identified as epitopes that bind HLA-A2 molecules and stimulate T cell responses. Modified agonist peptides with increased binding affinity and immunogenicity are also provided.
Claims Coverage
The claims cover methods of treating PAGE4-expressing cancers by administering immunogenic PAGE4 polypeptides or vectors encoding them, and compositions comprising recombinant viral vectors expressing the peptides and costimulatory molecules. The coverage includes specific peptide sequences, vector types, co-administration with costimulatory and immunostimulatory molecules, and methods of eliciting immune responses.
Method of treating PAGE4-expressing cancer using specific immunogenic polypeptides or encoding vectors
Administering to a subject a therapeutically effective amount of a PAGE4 polypeptide consisting of amino acids 16 to 25 of SEQ ID NO: 1 with specified substitutions (X1 as glutamine or tyrosine, X2 as glutamic acid or leucine), or a vector encoding this polypeptide, excluding vectors encoding the full-length PAGE4 (SEQ ID NO: 1).
Use of specific amino acid variants of PAGE4 polypeptides for treatment
Utilizing polypeptides with amino acids 16 to 25 of SEQ ID NO: 1 where X1 and X2 are defined amino acids: (a) X1 glutamine and X2 leucine, or (b) X1 tyrosine and X2 leucine, for therapeutic treatment of cancer.
Administration of vectors encoding immunogenic polypeptides via various viral or non-viral vector systems
Use of plasmid, yeast, and various viral vectors—including retrovirus, orthopox, avipox, fowlpox, vaccinia, adenoviral, herpes virus, alpha virus, baculovirus, Sindbis virus, poliovirus vectors—to deliver nucleic acids encoding the specified PAGE4 polypeptides.
Co-administration of recombinant viruses encoding immunogenic PAGE4 polypeptides and costimulatory molecules
Administering first recombinant virus encoding the PAGE4 immunogenic polypeptide together with a second recombinant virus encoding one or more costimulatory molecules such as B7-1, B7-2, LFA, or ICAM-1 to achieve coexpression in host cells.
Inclusion of immunostimulatory molecules in therapeutic compositions
The second recombinant virus may also encode immunostimulatory molecules like IL-2, ICAM-1, LFA-3, CD72, GM-CSF, TNF-α, IFN-γ, IL-12, or IL-6 to enhance immune response.
Pharmaceutical compositions and host cells containing vectors encoding immunogenic PAGE4 polypeptides
Vectors or plasmids encoding PAGE4 polypeptides comprising amino acids 59 to 68 of SEQ ID NO: 1 with specified substitutions are included, as are pharmaceutical compositions containing these vectors and host cells transformed therewith.
Methods of eliciting immune responses and enhancing immune activity using PAGE4 polypeptides and encoding nucleic acids
Administering immunogenic PAGE4 polypeptides or nucleic acids to induce immune responses, optionally with adjuvants or immunostimulatory molecules, and methods of infecting cells with vectors encoding these polypeptides for immunotherapy.
The claims comprehensively cover the use of specific truncated and modified PAGE4 polypeptides and their encoding nucleic acids or vectors for therapeutic purposes, including various vector systems and co-administration with costimulatory and immunostimulatory molecules. The claims also cover compositions, transformed cells, and methods of immune response induction against PAGE4-expressing cancers.
Stated Advantages
Immunogenic PAGE4 polypeptides and their agonist variants demonstrate enhanced binding affinity to HLA-A2 molecules and improved stability of peptide-MHC complexes, leading to stronger activation of cytotoxic T lymphocytes.
Use of agonist peptides such as P16-1 results in higher levels of immune effector functions, including production of IFN-γ, TNF-α, IL-2, Granzyme B, and chemokines like lymphotactin, which enhance anti-tumor immune responses.
T-cell lines generated with agonist peptides lyse PAGE4-expressing tumor cells specifically and effectively in an HLA-A2 restricted manner, supporting their potential as therapeutic agents.
The agonist peptides increase the frequency of PAGE4-specific CD8+ T cells in patients, which can improve the sensitivity of immunoassays and the efficacy of immunotherapies.
Documented Applications
Use of immunogenic PAGE4 polypeptides and analogs for immunotherapy of reproductive cancers, including prostate, uterine, cervical, and testicular cancers.
Development of diagnostic assays to detect PAGE4 expression in reproductive cancers.
Vaccination strategies using synthetic peptides, viral vectors, or antigen-pulsed dendritic cells to induce immune responses against PAGE4-expressing tumors.
Combination therapies administering PAGE4 immunogenic peptides or vectors together with costimulatory molecules, cytokines, or chemotherapeutic agents to enhance anti-tumor efficacy.
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