Immunogenic peptides and methods of use
Inventors
Schlom, Jeffrey • Tsang, Kwong-Yok • Pastan, Ira H
Assignees
National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-7910692-B2
Publication Date
2011-03-22
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 provides immunogenic PAGE4 polypeptides derived from the PAGE4 gene, which is expressed in reproductive tissues and reproductive cancers such as prostate, uterine, cervical, and testicular cancer. The disclosed polypeptides comprise at most ten consecutive amino acids of the PAGE4 consensus sequence, including specific regions from amino acids 16 to 25, 59 to 68, or 84 to 92, with defined possible amino acid variations at designated positions (X1 to X8). Polynucleotides encoding these polypeptides, vectors harboring these nucleic acids, and host cells transformed with these vectors are also provided.
The invention addresses the problem that existing treatments for cancers of reproductive organs are often insufficient, especially since many are diagnosed at late stages when metastases have occurred, and current therapies such as surgery, radiation, or hormone therapy can be incomplete or lead to recurrence. There is a need for new methods to enhance the immune response, particularly cytotoxic T lymphocyte (CTL) responses, to tumor-associated antigens to aid in diagnosis and therapy.
The disclosed immunogenic PAGE4 polypeptides can be used to induce immune responses against PAGE4-expressing cells, serving as the basis for diagnostic assays and immunotherapeutic interventions. Compositions including these polypeptides, their encoding nucleic acids, viral vectors, and host cells can be administered alone or in combination with agents such as costimulatory molecules (B7-1, B7-2) or cytokines, and combined with traditional cancer therapies to treat subjects with reproductive cancers.
Claims Coverage
The claims include 39 claims with multiple inventive features focused mainly on isolated polypeptides derived from PAGE4, nucleic acids encoding these polypeptides, recombinant vectors and viruses, compositions coexpressing costimulatory molecules, pharmaceutical compositions, methods of eliciting immune responses, and methods of inhibiting cancer cell growth.
Isolated PAGE4-derived polypeptides with specified amino acid variations
Isolated polypeptides comprising at most ten consecutive amino acids of the PAGE4 consensus sequence (SEQ ID NO: 1), with defined amino acid substitutions at positions X1 to X8, specifically including sequences from amino acids 16 to 25, 59 to 68, or 84 to 92 with particular residue variations.
Isolated nucleic acids encoding the PAGE4-derived polypeptides
Isolated polynucleotides encoding the isolated PAGE4 polypeptides, operably linked to promoters for expression.
Vectors comprising nucleic acids encoding PAGE4 polypeptides
Vectors including plasmid or viral vectors selected from retrovirus, orthopox, avipox, fowlpox, capripox, suipox, adenoviral, herpes, alpha virus, baculovirus, Sindbis, vaccinia, and poliovirus vectors, comprising polynucleotides encoding the PAGE4 immunogenic peptides.
Compositions comprising recombinant viruses coexpressing PAGE4 polypeptides and costimulatory molecules
Compositions including a first recombinant virus encoding a PAGE4 polypeptide and a second recombinant virus encoding one or more costimulatory molecules (B7-1, B7-2, LFA, or ICAM-1), capable of coinfecting a host cell resulting in coexpression.
Pharmaceutical compositions comprising the PAGE4 polypeptides, vectors, or host cells
Pharmaceutical compositions comprising therapeutically effective amounts of the PAGE4 polypeptides, nucleic acids, vectors, or host cells transformed with the vectors, with pharmaceutically acceptable carriers.
Methods of eliciting immune responses to PAGE4
Methods for eliciting an immune response in a subject by administering therapeutically effective amounts of the PAGE4 polypeptides or nucleic acids, optionally with adjuvants or immunostimulatory molecules such as IL-2, RANTES, GM-CSF, TNF-α, IFN-γ, G-CSF, and others.
Methods of enhancing immune response via in vitro infection and administration of infected cells
Methods comprising infecting cells in vitro with viral vectors encoding PAGE4 polypeptides and administering the infected cells to subjects to enhance immune responses, with the infected cells being dendritic cells or tumor cells.
Methods of inhibiting growth of reproductive cancer cells using activated CTLs
Methods involving culturing cytotoxic T lymphocytes or precursors with the PAGE4 polypeptides and antigen presenting cells to produce activated CTLs that recognize and inhibit reproductive cancer cells including prostate, testicular, or uterine cancer cells.
Methods of detecting PAGE4-specific CD8 T cells using tetramer reagents
Methods for detecting CD8+ T cells recognizing PAGE4 by contacting subject peripheral blood mononuclear cells with tetrameric complexes of the PAGE4 polypeptides bound to MHC class I molecules and detecting bound cells.
The claims comprehensively cover isolated immunogenic PAGE4 polypeptides with specific amino acid variations, nucleic acids encoding them, recombinant vectors including viral vectors, compositions coexpressing costimulatory molecules, pharmaceutical formulations, methods to elicit immune responses, enhance immune activation via infected cell administration, inhibit reproductive cancer cell growth, and to detect PAGE4-specific CD8+ T cells.
Stated Advantages
Immunogenic PAGE4 polypeptides can enhance the activation of cytotoxic T lymphocytes against cancers expressing PAGE4, improving immunotherapy possibilities.
Peptide modifications (agonist peptides) increase binding affinity to HLA-A2 and stability, leading to stronger immune responses and better tumor cell lysis.
Use of costimulatory molecules in recombinant viral vector compositions enhances immune response amplification.
The identified epitopes facilitate development of sensitive immunoassays to monitor immune responses in cancer vaccine clinical trials.
Documented Applications
Induction of immune responses against reproductive cancers, including prostate, uterine, cervical, and testicular cancer, by administering immunogenic PAGE4 polypeptides or nucleic acids encoding them.
Use of the PAGE4-derived immunogenic peptides for diagnostic assays to detect PAGE4 expression in cancers.
Treatment of prostate and other reproductive cancers by compositions comprising recombinant viral vectors encoding PAGE4 polypeptides and costimulatory molecules.
In vitro activation of cytotoxic T lymphocytes via incubation with PAGE4 peptides and antigen presenting cells to produce effectors that inhibit reproduction cancer cell growth.
Detection of PAGE4-specific CD8+ T cells in subjects using MHC class I tetramer complexes of PAGE4 peptides for analysis in diagnostics or monitoring.
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