title: Heteroclitic CD33 peptide with enhanced anti-acute myeloid leukemic immunogenicity.
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 and YIISGDSPL 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 naive (CD45RA(+)/CCR7(+))-CD8(+)cells. In addition, T-cell clones specific to the YLISGDSPV 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 heteroclitic YLISGDSPV CD33 epitope that is a promising candidate for immunotherapy targeting AML.
authors.affiliation: Section of Bone Marrow Transplant and Cell Therapy, Rush University Medical Center, Chicago, Illinois, USA. jooeun_bae@dfci.harvard.edu
authors.forename: Jooeun
authors.initials: J
authors.lastname: Bae
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Martinson
authors.forename: Hans G
authors.initials: HG
authors.lastname: Klingemann
mesh_terms: D000208:Acute Disease; D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000737:chemistry / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007951:Leukemia, Myeloid / Q000276:immunology*; D010446:Peptide Fragments; D063268:Sialic Acid Binding Ig-like Lectin 3; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D063268:Sialic Acid Binding Ig-like Lectin 3