Human cytotoxic T-lymphocyte epitope and its agonist epitope from the non-variable number of tandem repeat sequence of MUC-1
Inventors
Schlom, Jeffrey • Tsang, Kwong-Yok
Assignees
US Department of Health and Human Services
Publication Number
US-8957192-B2
Publication Date
2015-02-17
Expiration Date
2024-12-10
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Abstract
Novel MUC-1 epitopes outside the VNTR region are identified. In addition, the first agonist epitope of MUC-1 is described. The employment of agonist epitopes in peptide, protein and vector-based vaccine may well aid in the development of effective vaccines for a range of human cancers.
Core Innovation
The invention identifies novel human cytotoxic T-lymphocyte (CTL) epitopes of the tumor-associated antigen MUC-1 located outside the traditionally immunogenic variable number of tandem repeat (VNTR) region. It also discloses the first agonist epitope of MUC-1 that elicits a stronger immune response compared to the native peptide. The agonist epitopes can be employed in peptide, protein, and vector-based vaccines to potentially enhance the development of effective vaccines against a range of human cancers.
The problem solved by this invention arises from the limitations of current cancer treatments such as radiation therapy and chemotherapy, which can have particularly adverse effects and lack specificity. There is a recognized need for treatments that are more specific, less toxic, and capable of providing long-lasting protection against tumors. Particularly, there is limited knowledge regarding immunogenic epitopes outside the VNTR region of MUC-1. By identifying non-VNTR CTL epitopes and generating enhancer agonist epitopes with higher binding avidity to HLA molecules, this invention addresses the need for more effective and targeted immunotherapies for MUC-1 positive tumors.
Claims Coverage
The claims cover isolated nucleic acid molecules encoding agonist polypeptides derived from MUC-1, vectors expressing these polypeptides, host cells transformed therewith, and methods for generating immune responses and treating MUC-1 tumors.
Isolated nucleic acid molecules encoding MUC-1 agonist polypeptides up to 12 amino acids in length
The nucleic acid molecules consist of sequences encoding any of the agonist polypeptides comprising the amino acid sequences of SEQ ID NOs:14-19, including specifically the sequence of SEQ ID NO:19.
Nucleic acid vectors expressing agonist polypeptides under inducible promoters
Vectors contain one or more nucleic acid sequences encoding polypeptides of up to 12 amino acids selected from SEQ ID NOs:1, 14-19, operably linked to inducible promoters which may be tissue specific. The vector may be a viral vector or plasmid.
Recombinant vectors encoding agonist MUC-1 polypeptides
Recombinant vectors comprising nucleic acid sequences encoding agonist polypeptides up to 12 amino acids in length with sequences selected from SEQ ID NOs:1, 14-19.
Host cells transformed with vectors encoding agonist polypeptides
Host cells comprising recombinant vectors with nucleic acid sequences encoding the agonist polypeptides as above.
Methods for generating immune responses to MUC-1 tumor antigen
Methods comprise administering at least one isolated nucleic acid molecule or vector encoding the agonist polypeptides of SEQ ID NOs:1, 14-19, in therapeutically effective doses sufficient to generate a cellular immune response, including cytotoxic T cell responses.
Methods for treating MUC-1 tumors using transduced dendritic cells
Methods involve isolating dendritic cells from a subject with cancer, transducing the cells with recombinant vectors encoding the agonist polypeptides, and administering the transduced dendritic cells to treat the subject.
The claims collectively cover nucleic acid molecules, vectors, transformed host cells, and therapeutic methods involving agonist polypeptides derived from MUC-1 sequences outside the VNTR region, providing compositions and approaches for enhancing immune responses and treating MUC-1 positive tumors.
Stated Advantages
Agonist polypeptides stimulate stronger immune responses than native peptides, including higher binding avidity to HLA molecules and greater IFN-γ production by T cells.
Use of agonist epitopes may overcome the poor immunogenicity of tumor antigens and enhance activation and cytotoxicity of tumor-specific T cells.
Vaccine compositions expressing multiple transgenes including agonist epitopes can address tumor antigen heterogeneity, potentially eliciting broader and more effective anti-tumor responses.
Dendritic cells infected with vectors encoding agonist polypeptides and co-stimulatory molecules induce robust activation of antigen-specific T cells.
Documented Applications
Use of agonist epitopes in peptide, protein, and vector-based vaccines for the development of effective vaccines for a range of human cancers, including solid tumors, leukemias, and lymphomas.
Treatment of subjects suffering from or susceptible to MUC-1 positive tumors by administration of peptides, nucleic acids, or dendritic cells transduced with vectors encoding agonist polypeptides.
Generation of immune responses, including cytotoxic T cell responses, by administering isolated nucleic acid molecules or vectors encoding MUC-1 agonist polypeptides.
Ex vivo transduction of dendritic cells with vectors expressing agonist polypeptides and optionally co-stimulatory molecules, followed by administration to subjects to induce anti-tumor immunity.
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