Ii-Key/HPV16 E7 hybrid peptide immunotherapy for HPV16+ cancers.

Abstract

Activation of antigen-specific CD4+ T cells is critical for vaccine design. We have advanced a novel technology for enhancing activation of antigen-specific CD4+ T helper cells whereby a fragment of the MHC class II-associated invariant chain (Ii-Key) is linked to an MHC class II epitope. An HLA-DR4-restricted HPV16 E7 epitope, HPV16 E7(8-22), was used to create a homologous series of Ii-Key/HPV16 E7 hybrids testing the influence of spacer length on in vivo enhancement of HPV16 E7(8-22)-specific CD4+ T lymphocyte responses. HLA-DR4-tg mice were immunized with Ii-Key/HPV16 E7(8-22) hybrids or the epitope-only peptide HPV16 E7(8-22). As measured by IFN-gamma ELISPOT assay of splenocytes from immunized mice, one of the Ii-Key/HPV16 E7(8-22) hybrids enhanced epitope-specific CD4+ T cell activation 5-fold compared to the HPV16 E7(8-22) epitope-only peptide. We further demonstrated that enhanced CD4+ T cell activation augments the CTL activity of a H-2D(b)-restricted HPV16 E7(49-57) epitope in HLA-DR4+ mice using an in vivo CTL assay. Binding assays indicated that the Ii-Key/HPV16 hybrid has increased affinity to HLA-DR4+ cells relative to the epitope-only peptide, which may explain its increased potency. In summary, Ii-Key hybrid modification of the HLA-DR4-restricted HPV16 E7(8-22) MHC class II epitope generates a potent immunotherapeutic peptide vaccine that may have potential for treating HPV16+ cancers in HLA-DR4+ patients.

• Authors: Minzhen Xu, Xueqing Lu, Margaret Sposato, John W Zinckgraf, Shuzhen Wu, Eric von Hofe
• Journal: Vaccine (Vaccine) Vol. 27 Issue 34 Pg. 4641-7 (Jul 23 2009) ISSN: 1873-2518 [Electronic] Netherlands
• PMID: 19520206 (Publication Type: Journal Article)

Chemical References

• Antigens, Differentiation, B-Lymphocyte
• Histocompatibility Antigens Class II
• Immunologic Factors
• Oncogene Proteins, Viral
• Papillomavirus E7 Proteins
• Recombinant Fusion Proteins
• invariant chain
• oncogene protein E7, Human papillomavirus type 16
• Interferon-gamma

Topics

• Animals
• Antigens, Differentiation, B-Lymphocyte (genetics, therapeutic use)
• CD4-Positive T-Lymphocytes (immunology)
• Cytotoxicity Tests, Immunologic
• Female
• Histocompatibility Antigens Class II (genetics, therapeutic use)
• Immunologic Factors (genetics, pharmacology, therapeutic use)
• Immunotherapy (methods)
• Interferon-gamma (metabolism)
• Mice
• Mice, Inbred C57BL
• Neoplasms (immunology)
• Oncogene Proteins, Viral (genetics, therapeutic use)
• Papillomavirus E7 Proteins
• Recombinant Fusion Proteins (genetics, pharmacology, therapeutic use)
• T-Lymphocytes, Cytotoxic (immunology)
• Uterine Cervical Neoplasms (immunology)