Ii-Key/MHC class II epitope hybrids: a strategy that enhances MHC class II epitope loading to create more potent peptide vaccines

Abstract

Life-threatening diseases, such as cancer and pandemic influenza, demand new efforts towards effective vaccine design. Peptides represent a simple, safe and adaptable basis for vaccine development; however, the potency of peptide vaccines is insufficient in most cases for significant therapeutic efficacy. Several methods, such as Ligand Epitope Antigen Presentation System and ISCOMATRIX, have been developed to enhance the potency of peptide vaccines. One way of increasing the loading of MHC class II peptides occurs through the use of Ii-Key technology. Ii-Key (LRMK), a portion of the MHC class II-associated invariant chain (Ii), facilitates the direct loading of epitopes to the MHC class II molecule groove. Linking the Ii-Key moiety via a simple polymethylene bridge to an MHC class II epitope, to generate an Ii-Key/MHC class II epitope hybrid, greatly enhances the vaccine potency of the tethered epitope. The combination of such Ii-Key/MHC class II epitope hybrids with MHC class I epitope-containing peptides might generate a potent peptide vaccine for malignancies and infectious diseases. The Ii-Key hybrid technology is compared with other methods that enhance the potency of a peptide vaccine.

A new era in anticancer peptide vaccines

“…43 By using the Ii-Key/ HER-2/neu(776-790) peptide, a series of Ii-Key/epitope hybrids were designed and screened in vitro using peripheral blood mononuclear cells from cancer patients who had various types of HER-2-positive tumors to identify a candidate hybrid (AE37) for clinical trials. 43,45 Furthermore, CD4-positive T cells from AE37-immunized mice potentiated CD8-positive T cells to recognize and lyse autologous tumor cells more efficiently in vitro 43,45 and in vivo. [45][46][47] All of the aforementioned studies paved the way for clinical trials of AE37 in patients with breast cancer.…”

“…43,45 Furthermore, CD4-positive T cells from AE37-immunized mice potentiated CD8-positive T cells to recognize and lyse autologous tumor cells more efficiently in vitro 43,45 and in vivo. [45][46][47] All of the aforementioned studies paved the way for clinical trials of AE37 in patients with breast cancer. 48,49 Large Tumors Induce Strong Immunosuppression: The Concept of Vaccinating During the Early Stages of Tumor Formation It has been demonstrated that bulky tumors generate strong tolerizing conditions within their microenvironment that limit effective immunotherapy.…”

“…Ii-Key is derived from the MHC class IIassociated invariant chain (Ii protein) and catalyzes binding of the linked epitope to the MHC class II molecule, thereby enhancing the overall potency of presentation. [45][46][47] More recently, studies have indicated that, in addition to increasing binding to the MHC class II molecule, the presence of the Ii-Key moiety also may trigger the release of activating cytokines and chemokines from DCs after class II binding (unpublished data). In several studies, IiKey hybrid peptides demonstrated significantly increased potency over the unmodified epitope peptide in both in vitro and in vivo vaccine studies as determined by the antigen-specific stimulation of T cells.…”

“…41,42 We also observed strong immunogenicity with HER-2/neu(776-790), which is an extended analog of the p776 to p788 peptide. [43][44][45] CD4-positive T cells primed with the p776 to p790 peptide exhibited an extensive capacity to synergize with syngeneic CTLs for the rejection of HER-2/neu-positive tumors. [43][44][45] Both the p776 to p790 peptide and the p776 to p788 peptide encompass in their sequences the nonamers GVGSPYVSRL (p776-p784), VGSPYVSRL (p777-p785), and PYVSRLLGI (p780-788), which bind with intermediate to high affinity to the HLA-A2.1/A68, HLA-A11, and HLA-A3 alleles, respectively.…”

“…[43][44][45] CD4-positive T cells primed with the p776 to p790 peptide exhibited an extensive capacity to synergize with syngeneic CTLs for the rejection of HER-2/neu-positive tumors. [43][44][45] Both the p776 to p790 peptide and the p776 to p788 peptide encompass in their sequences the nonamers GVGSPYVSRL (p776-p784), VGSPYVSRL (p777-p785), and PYVSRLLGI (p780-788), which bind with intermediate to high affinity to the HLA-A2.1/A68, HLA-A11, and HLA-A3 alleles, respectively. Thus, the p776 to p790 peptide may function as a multipeptide vaccine that contains overlapping T h and CTL epitope motifs, thereby acting as a powerful inducer of antitumor immune responses.…”