Heteroclitic CD33 Peptide With Enhanced Anti-Acute Myeloid Leukemic Immunogenicity

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Abstract
The goal of these studies was to engineer a synthetic CD33 peptide with enhanced immunogenicity for the induction of acute myeloid leukemia (AML)-specific CTLs. Eight modified CD33 peptides YLISGDSPV,YIGSGDSPV,YIIIGDSPV,YIILGDSPV,YIISGISPV,YIISGDLPV,YIISGDSWV andYIISGDSPL were designed for increased HLA-A2.1 or T cell receptor affinity and compared with the native CD3365–73 peptide, AIISGDSPV, for enhanced immunogenicity. The YLISGDSPV peptide was found to be the most immunogenic epitope producing highly cytolytic CTLs against AML target cells. The CTLs generated withYLISGDSPV peptide showed CD33 peptide-specificity through targeting of both native (AIISGDSPV) and modified (YLISGDSPV) peptide presenting EBV-BLCL. The CTL cultures displayed a distinct phenotype consisting of a high percentage of activated memory (CD69+/CD45RO+)-CD8+and a low percentage of naïve (CD45RA+/CCR7+)-CD8+cells. In addition, T-cell clones specific to theYLISGDSPV peptide were isolated and characterized to target AML cells. The clones exhibited both HLA-A2.1-restricted and AML cell-specific cytotoxicity that was mediated through a granule-dependent pathway. More importantly, the CTL clones did not lyse or inhibit the proliferation of normal CD34+ progenitor cells. In conclusion, we report on the identification of a highly immunogenic heterocliticYLISGDSPV CD33 epitope that is a promising candidate for immunotherapy targeting AML.