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Publication Number
US-8263757-B2
Publication Date
2012-09-11
Expiration Date
Abstract
The present invention relates to the discovery of novel T cell epitopes of the human HER-2/Neu protein that is promiscuous for at least 25 different HLA-DR alleles. The invention also relates to compositions that contain one of the novel epitopes or a fusion peptide of such a epitope and a heterologous polypeptide. Further disclosed herein is the use of the epitopes or their fusion peptides, and compositions containing the epitopes or their fusion peptides.
Core Innovation
The disclosed subject matter provides human HER-2/Neu CD4 T cell epitopes with broad HLA-DR promiscuity. The epitopes are presentable by at least 25 HLA-DRB1 alleles, and the disclosure centers on HERp270-284 with SEQ ID NO:2 (ALVTYNTDTFESMPN) within HER-2/Neu residues 270-284 and related region variants including the HER-2/Neu residues 268-286 region.
HLA-DR restriction is confirmed using blocking antibodies, and epitope mapping is performed using truncated 9–11mer peptides to identify minimal core epitopes. The centered epitope is naturally processed, and functional evidence includes IFNγ and IL-2 responses induced in association with a HER-2/Neu-specific T cell response, including a referenced T cell clone (HER500.23c21).
The disclosure further provides isolated peptides, fusion peptides with a heterologous polypeptide, nucleic acids encoding the epitope or fusion peptide, expression cassettes, recombinant viral vector expression cassettes, and host cells containing the nucleic acid or expression cassette. Immunogenic compositions and approaches are also described for inducing and detecting HER-2/Neu-specific T cell immune responses.
Claims Coverage
The provided claim set includes two independent claims. Across these, the claims cover 2 inventive features: isolated nucleic acids encoding specified HER-2/Neu epitope amino acid sequences, and isolated nucleic acids encoding fusion peptides that combine those epitope sequences with a heterologous polypeptide.
Isolated nucleic acid encoding specified HER-2/Neu epitope sequences
An isolated nucleic acid consisting of a polynucleotide sequence encoding the amino acid sequence of SEQ ID NOs: 2, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 31.
Isolated nucleic acid encoding fusion peptide with heterologous polypeptide
An isolated nucleic acid comprising a polynucleotide sequence encoding a fusion peptide consisting of the amino acid sequence of SEQ ID NOs: 2, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 31 and a heterologous polypeptide.
Overall, the claims focus on nucleic-acid embodiments for HER-2/Neu epitope sequences and nucleic-acid embodiments encoding fusion peptides that attach those epitope sequences to a heterologous polypeptide, including a dependent embodiment specifying GM-CSF.
Stated Advantages
Broad HLA-DR promiscuity, presentable by at least 25 HLA-DRB1 alleles.
Functional T cell responses are provided, including IFNγ and IL-2 responses.
The centered epitope is naturally processed.
Documented Applications
Inducing and detecting HER-2/Neu-specific T cell immune responses, including IFNγ/IL-2-associated responses.
Immunogenic compositions and embodiments including isolated peptides and fusion peptides, as well as nucleic acids, expression cassettes, recombinant viral vector expression cassettes, and host cells for use in the described immune-response context.
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