Heteroclitic CD33 peptide with enhanced anti-acute myeloid leukemic immunogenicity

Clin Cancer Res. 2004 Oct 15;10(20):7043-52. doi: 10.1158/1078-0432.CCR-04-0322.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Antigens, CD / chemistry
  • Antigens, CD / immunology*
  • Antigens, Differentiation, Myelomonocytic / chemistry
  • Antigens, Differentiation, Myelomonocytic / immunology*
  • HLA-A2 Antigen / immunology*
  • Humans
  • Immunotherapy
  • Leukemia, Myeloid / immunology*
  • Peptide Fragments
  • Sialic Acid Binding Ig-like Lectin 3
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD33 protein, human
  • HLA-A2 Antigen
  • Peptide Fragments
  • Sialic Acid Binding Ig-like Lectin 3