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Publication Number
US-7972602-B2
Publication Date
2011-07-05
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 invention relates to HER-2/Neu-derived, HLA-DRB1-promiscuous CD4 T cell epitopes, including HERp270-284 (SEQ ID NO:2) within residues 270-284 and related peptides within residues 268-286 (SEQ ID NO:1). These epitopes are recognized by a patient-derived CD4+ T cell clone designated HER500.23c21.
The epitopes are HLA-DR restricted and are shown to be blocked by anti-HLA-DR. The epitopes are presented by at least 25 different HLA-DRB1 alleles across multiple DR serological families, supporting HLA-DRB1-promiscuous presentation.
Peptides derived from exogenous protein are described as naturally processed and used as universal helper epitopes. The invention further covers compositions comprising the epitopes or fusion peptides with a heterologous polypeptide, including GM-CSF, and includes related nucleic acids, expression cassettes/host cells, and functional assays.
Example evidence is described using IFNγ/IL-2 readouts and assays addressing MHC restriction and promiscuity, including ELISPOT and proliferation assay formats, with antigen-presenting cells referenced in the description, including EBV-LcL and PBMC.
Claims Coverage
The independent claim covers an isolated peptide defined by having an amino acid sequence equal to one of the listed SEQ ID NOS (2, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 31). The claim set includes additional inventive features for fusion peptides with a heterologous polypeptide, including GM-CSF, and compositions with physiologically acceptable excipients and antigen-presenting cells with peptide–MHC complexes on the cell surface. Inventive features across the independent claim include peptide sequence identity, fusion construct form, specific heterologous polypeptide selection, and formulation/presentation context.
Isolated peptide defined by SEQ ID NOS sequence
An isolated peptide consisting of the amino acid sequence of SEQ ID NOS:2, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 31.
Fusion peptide with a heterologous polypeptide
A fusion peptide formed by fusing the peptide to a heterologous polypeptide.
Fusion peptide using GM-CSF as the heterologous polypeptide
The fusion peptide characterized in that the heterologous polypeptide is granulocyte-macrophage colony-stimulating factor (GM-CSF).
Composition including an antigen-presenting cell with peptide–MHC on the cell surface
A composition further includes an antigen-presenting cell where the peptide forms a complex with a major histocompatibility complex (MHC) molecule on the cell surface.
Composition with a physiologically acceptable excipient
A composition is claimed that includes the peptide or the fusion peptide together with a physiologically acceptable excipient.
Overall, the claim coverage centers on an isolated peptide defined by amino acid sequence identity to specified SEQ ID NOS, with further coverage for fusion-peptide constructs using a heterologous polypeptide, specifically GM-CSF, and formulations that optionally include physiologically acceptable excipients and antigen-presenting cells presenting a peptide–MHC complex on the cell surface.
Stated Advantages
HLA-DRB1-promiscuous presentation across multiple HLA-DRB1 alleles (at least 25).
HLA-DR restricted recognition, blocked by anti-HLA-DR.
Peptides can be naturally processed from exogenous protein as universal helper epitopes.
Documented Applications
Use as HER-2/Neu-derived HLA-DRB1-promiscuous CD4 T cell epitopes recognized by a patient-derived CD4+ T cell clone (HER500.23c21).
Compositions comprising the epitopes or fusion peptides, including GM-CSF, for functional evaluation using IFNγ/IL-2 readouts and assays addressing MHC restriction and promiscuity.
Experimental presentation on antigen-presenting cells, including EBV-LcL and PBMC, where the peptide forms a peptide–MHC complex on the cell surface.
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