Development of agonist epitopes of the human papillomavirus
Inventors
Schlom, Jeffrey • Tsang, Kwong-Yok
Assignees
US Department of Health and Human Services
Publication Number
US-11311613-B2
Publication Date
2022-04-26
Expiration Date
2037-11-06
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Abstract
The invention provides HPV agonist epitopes, which can be used as a peptide, polypeptide (protein), and/or in a vaccine or other composition for the prevention or therapy of HPV infection and/or cancer. The invention further provides a nucleic acid encoding the peptide or polypeptide (protein), a vector comprising the nucleic acid, a cell comprising the peptide, polypeptide (protein), nucleic acid, or vector, and compositions thereof.
Core Innovation
The invention provides novel HPV agonist epitopes, which can be used as peptides or polypeptides (proteins) and incorporated into vaccines or other compositions for the prevention or therapy of HPV infection and HPV-associated cancers. These agonist epitopes include specific amino acid sequences represented by SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, derived from HPV-16 E6 and E7 proteins. The therapeutic compositions can further include nucleic acids encoding these peptides or polypeptides, vectors comprising such nucleic acids, cells expressing these peptides, polypeptides, nucleic acids, or vectors, and related pharmaceutical formulations.
The invention addresses the problem that, as of the filing date, no therapeutic HPV vaccine approved by the FDA existed that could effectively enhance the lysis of human tumor cells caused by HPV infection. HPV has been associated with several cancers, including cervical, anal, and head and neck cancers; therefore, there is a need for improved therapeutic interventions to treat or prevent HPV infection and related malignancies.
Claims Coverage
The patent claims cover a range of inventive features centered on peptides, nucleic acids, vectors, cells, compositions, and methods related to HPV agonist epitopes SEQ ID NO: 2 and SEQ ID NO: 3, with 25 main inventive features.
Peptides comprising specific HPV agonist epitopes
Claims a peptide comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3, with no more than 20 amino acid residues; includes peptides consisting exactly of these sequences.
Nucleic acids encoding the peptides
Claims nucleic acid molecules encoding the peptides of SEQ ID NO: 2 or SEQ ID NO: 3.
Vectors comprising the nucleic acids
Claims vectors that comprise the nucleic acid encoding one or more copies of the peptides.
Cells comprising peptides, nucleic acids, or vectors
Claims cells that contain (i) the peptides, (ii) nucleic acids encoding the peptides, or (iii) vectors comprising such nucleic acids, including human cells or antigen-presenting/tumor cells.
Pharmaceutical compositions comprising the peptides, nucleic acids, vectors, or cells
Claims compositions containing one or more peptides, nucleic acids, vectors, or cells along with a pharmaceutically acceptable carrier.
Compositions including immunostimulatory/regulatory molecules
Claims compositions further comprising immunostimulatory or regulatory molecules such as interleukins (e.g., IL-2, IL-12), interferon gamma, TNF-alpha, B7.1, ICAM-1, LFA-3, and checkpoint inhibitors, enhancing immune response.
Compositions with chemotherapeutic or antiviral agents
Claims compositions further comprising chemotherapeutic drugs, radioactive agents, antimetabolites, hormones, antibiotics, antiviral drugs, antifungal drugs, cyclophosphamide, and similar agents.
Compositions with specified anticancer agents
Claims compositions further comprising selected anticancer agents including alkylating agents, folate antagonists, purine and pyrimidine antagonists, taxanes, monoclonal antibodies, and others known in the art.
Compositions containing adjuvants
Claims compositions further comprising adjuvants such as alum, aluminum salts, incomplete Freund's adjuvant, saponins like QS21, monophosphoryl lipid A, and RIBI DETOX™ to enhance immunogenicity.
Compositions including granulocyte monocyte colony stimulating factor
Claims compositions further comprising GM-CSF to enhance antigen processing and presentation by dendritic cells.
Methods of inhibiting HPV infection
Claims methods of administering a therapeutically effective amount of the composition to subjects to inhibit HPV infection.
Methods of enhancing immune response against HPV-associated cancer
Claims methods of administering a therapeutically effective amount of the composition to subjects to enhance immune response against HPV-associated cancers.
Methods of inhibiting HPV-associated cancer using cytotoxic T lymphocytes
Claims methods involving ex vivo stimulation of lymphocytes with the composition to generate cytotoxic T lymphocytes followed by administering these cells to inhibit HPV-associated cancer.
Methods of inhibiting HPV-associated cancer using dendritic cells
Claims methods comprising isolation of dendritic cells, ex vivo treatment with the composition, and administration of treated dendritic cells to inhibit HPV-associated cancer.
Methods using peripheral blood mononuclear cells and dendritic cells
Claims methods involving isolation of PBMCs and dendritic cells, ex vivo treatment of dendritic cells with the composition, activation of PBMCs with treated dendritic cells, and administration of activated PBMCs to inhibit HPV-associated cancer.
Methods isolating T lymphocytes from activated PBMCs for administration
Claims methods extending the above by isolating T lymphocytes from activated PBMCs ex vivo and administering them to inhibit HPV-associated cancer.
The claimed inventive features encompass peptides of specific HPV agonist epitopes, their encoding nucleic acids, vectors, cells expressing these elements, pharmaceutical compositions including immunostimulatory molecules and chemotherapeutics, and a suite of therapeutic methods for inhibiting HPV infection and HPV-associated cancers by various administration and cell-based approaches.
Stated Advantages
The agonist epitopes provide enhanced binding to HLA-A2 molecules and superior activation of cytotoxic T lymphocytes compared to native epitopes.
The peptides and compositions enable improved lysis of HPV-positive tumor cells, thereby potentially increasing therapeutic efficacy.
The invention allows for multiple approaches, including direct vaccination and ex vivo cell-based therapies, broadening clinical utility.
Incorporation of immunostimulatory molecules and adjuvants further enhances immune response effectiveness.
Documented Applications
Use as vaccines or therapeutic compositions for prevention or treatment of HPV infection.
Therapeutic treatment and prevention of HPV-associated cancers including cervical, anal, and head and neck cancers.
Methods for enhancing immune responses against HPV-associated cancers via administration of peptides, polypeptides, nucleic acids, vectors, cells, or compositions thereof.
Ex vivo stimulation of lymphocytes or dendritic cells followed by adoptive transfer to inhibit HPV-associated cancers.
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