Native and agonist CTL epitopes of the MUC1 tumor antigen
Inventors
Schlom, Jeffrey • Tsang, Kwong-Yok
Assignees
US Department of Health and Human Services
Publication Number
US-10138271-B2
Publication Date
2018-11-27
Expiration Date
2033-01-03
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Abstract
The invention provides peptides comprising a human cytolytic T lymphocyte (CTL) epitope from the human tumor-associated antigen (TAA) mucin 1 (MUC1) and analogs thereof, which can be used in vaccine prevention or therapy of cancer, as well as a nucleic acid encoding the peptide, a vector comprising the nucleic acid, a cell comprising the peptide, nucleic acid, or vector, and compositions thereof.
Core Innovation
The invention provides isolated peptides comprising human cytolytic T lymphocyte (CTL) epitopes from the human tumor-associated antigen mucin 1 (MUC1), specifically from the MUC1-C subunit, as well as analogs thereof. These peptides can be used in vaccine prevention or therapy of cancer. Additionally, the invention includes nucleic acids encoding these peptides, vectors comprising such nucleic acids, cells expressing the peptides or nucleic acids, and compositions thereof. The invention also encompasses methods of enhancing immune responses against MUC1-expressing cancers and inhibiting such cancers by administering these compositions or by ex vivo stimulation and adoptive transfer of immune cells.
The problem being addressed is the difficulty in achieving effective immune responses against MUC1-expressing tumors using previous vaccine strategies. While MUC1-N terminal subunits with variable number tandem repeat (VNTR) domains have been targeted, their shedding into the blood and clustered expression limit the immune response, especially in patients with advanced metastatic disease. MUC1-C, the membrane-anchored subunit of MUC1 that remains on tumor cells, is uniformly distributed over tumor surfaces and exhibits oncogenic functions. It is a promising target for CTL epitopes, but specific CTL epitopes and enhancer agonist peptides of MUC1-C have not been adequately identified or utilized prior to this invention.
Claims Coverage
The patent contains one independent claim focusing on a method of enhancing immune response using compositions featuring specific peptides or nucleic acids delivered via poxvirus vectors or liposomes.
Method of enhancing immune response using poxvirus vector or liposome-delivered peptide
A method of enhancing an immune response against a MUC1-expressing cancer in a subject by administering a therapeutically effective amount of a composition comprising (i) a poxvirus vector encoding a peptide with an amino acid sequence selected from SEQ ID NOs: 2, 5, 8, 10, 13, 14, 29, and 32, or (ii) a liposome comprising such peptides, resulting in enhanced immune response in the subject.
Use of specific poxvirus vector types in immune response enhancement
The poxvirus vector used in the method can be selected from orthopoxviruses, avipox, capripox, and suipox viruses.
Inclusion of multiple peptide sequences for enhanced immune response
The peptide in the composition can comprise two or more amino acid sequences from the group consisting of SEQ ID NOs: 2, 5, 8, 10, 13, 14, 29, and 32.
Inclusion of immunostimulatory/regulatory molecules in poxvirus vectors
The poxvirus vector can further comprise nucleic acids encoding one or more immunostimulatory or regulatory molecules, such as interleukins, interferons, tumor necrosis factors, B7 molecules, adhesion molecules, CD70, RANTES, G-CSF, OX-40L, 41BBL, anti-CTLA-4, or combinations thereof.
Prime and boost vaccination protocol with recombinant poxvirus vectors
A method involving administering to a subject first and second recombinant poxvirus vectors encoding the same MUC1 peptides with sequences selected from SEQ ID NOs: 2, 5, 8, 10, 13, 14, 29, and 32, enhancing an immune response. The vectors can carry immunostimulatory molecules and be selected from orthopox and avipox viruses, with the first vector being orthopox and the second avipox.
The claims cover methods of enhancing immune responses against MUC1-expressing cancers by administering compositions containing specific MUC1-C CTL epitopes or their analogs delivered via poxvirus vectors or liposomes, including specific vector types and immunostimulatory molecules, as well as prime-boost vaccination protocols using recombinant poxvirus vectors.
Stated Advantages
The peptides and their analogs induce higher affinity and more stable binding to HLA class I molecules, improving CTL activation.
Agonist peptides generate greater IFN-γ production and higher frequency of antigen-specific CD8+ T cells compared to native peptides.
The MUC1-C-specific T cells effectively lyse MUC1-expressing tumor cells in an antigen-specific and HLA-restricted manner.
Use of these peptides and vectors offers enhanced immunogenicity for preventing and treating multiple MUC1-expressing human carcinomas and hematologic malignancies.
Documented Applications
Vaccine prevention or therapy of cancers expressing MUC1, including ovarian, breast, pancreatic, colorectal, lung, thyroid, gastric, head and neck, and prostate cancers, as well as hematologic malignancies such as multiple myeloma and B-cell non-Hodgkin's lymphomas.
Methods of enhancing immune responses in subjects against MUC1-expressing tumors by direct administration of peptides, nucleic acids, vectors, or cells expressing these molecules.
Ex vivo stimulation of lymphocytes or dendritic cells with these peptides or nucleic acids, followed by adoptive transfer to inhibit MUC1-expressing cancers.
Use of prime-boost vaccination protocols with recombinant poxvirus vectors encoding the peptides and immunostimulatory molecules to increase cancer-specific immunity.
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