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Heteroclitic CD33 Peptide With Enhanced Anti-Acute Myeloid Leukemic Immunogenicity

Section of Bone Marrow Transplant and Cell Therapy, Rush University Medical Center, Chicago, Illinois

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 CD33_65–73 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.

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