vector-based vaccine may well aid in the development of effective vaccines for a range of human cancers; nucleic acid; agonist polypeptide derived from a mucin tumor antigen; genetic vaccine
Inventors
Schlom, Jeffrey • Tsang, Kwong-Yok
Assignees
US Department of Health and Human Services
Publication Number
US-7999071-B2
Publication Date
2011-08-16
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 MUC-1 epitopes outside the variable number of tandem repeat (VNTR) region and describes the first agonist epitope of MUC-1. It provides isolated nucleic acid molecules encoding agonist polypeptide antigens derived from tumor antigens such as MUC-1, which stimulate stronger immune responses compared to native polypeptides. Agonist polypeptides bind HLA molecules with higher avidity and promote enhanced cellular immune responses including cytotoxic T cell activation.
The problem addressed is the limited immunogenicity of tumor antigens outside the VNTR region of MUC-1 and the need for safer, more specific, and longer-lasting treatments for cancers overexpressing MUC-1. Current cancer therapies like radiation and chemotherapy have adverse effects, and there is a need for improved vaccines capable of eliciting robust immune responses to tumor antigens with reduced toxicity.
Claims Coverage
The claims contain two independent sets of inventive features: one directed to isolated polypeptides comprising specific short amino acid sequences, and another directed to therapeutic methods using these polypeptides for treating MUC-1 tumors and generating immune responses.
Isolated polypeptides comprising specific MUC-1 epitopes
An isolated polypeptide up to 12 amino acids in length comprising an amino acid sequence selected from SEQ ID NOs: 1 and 14-19, especially those comprising SEQ ID NO: 1, 14, 15, 16, 17, 18, or 19.
Methods of treating MUC-1 tumors using specific polypeptides
Methods for treating subjects suffering from a MUC-1 tumor by administering at least one of the isolated polypeptides comprising SEQ ID NOs: 1 and 14-19, wherein the demonstrated therapeutic effect is the treatment of the subject.
Methods of treating MUC-1 tumors using treated dendritic cells
Methods involving isolating dendritic cells from a subject suffering from cancer, treating these dendritic cells with at least one specified polypeptide (SEQ ID NOs: 1 and 14-19), and administering the treated dendritic cells back to the subject to achieve treatment.
Methods for generating immune responses to weakly immunogenic antigens
Methods comprising administration of at least one of the specified polypeptides fused to a weak immunogen (such as differentiation antigen, tumor antigen, carcinoembryonic antigen, viral antigen or self-antigen) to generate an enhanced immune response.
Methods of treating MUC-1 tumors by activating PBMCs with treated dendritic cells
Methods including isolating dendritic cells from a cancer patient, treating the dendritic cells with the specified polypeptides, activating peripheral blood mononuclear cells with these treated dendritic cells, and administering the activated PBMCs to the subject for treatment.
The claims primarily cover isolated short polypeptides comprising defined MUC-1 epitope sequences and various therapeutic methods using these polypeptides alone or via treated dendritic cells to generate enhanced immune responses against MUC-1 tumors, including treatment protocols and immune activation strategies.
Stated Advantages
The agonist epitopes generate stronger immune responses compared to native peptides, including higher binding affinity to HLA molecules and enhanced induction of IFN-γ production by T cells.
Vaccines expressing multiple transgenes (such as CEA and MUC-1 combined) help overcome antigenic heterogeneity of tumors.
Vectors and dendritic cells expressing agonist polypeptide epitopes lead to activation and expansion of cytotoxic T cells with improved tumor cell lysis.
Documented Applications
Treatment of MUC-1 positive human cancers such as ovarian, breast, pancreas, colorectal and prostate carcinomas, multiple myeloma and some B-cell non-Hodgkin lymphomas.
Generation of cellular immune responses including cytotoxic T cell, T helper cell and B cell responses against tumor antigens.
Use of dendritic cells transduced with vectors expressing MUC-1 agonist epitopes and costimulatory molecules for immunotherapy.
Development of peptide, protein and vector-based vaccines for eliciting stronger immune responses to tumor antigens.
Methods for generating immune responses to weakly immunogenic antigens by fusing high avidity agonist polypeptides to the weak immunogens.
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