In vivo efficacy of the recombinant anti-CD64 immunotoxin H22(scFv)-ETA' in a human acute myeloid leukemia xenograft tumor model

Int J Cancer. 2011 Sep 1;129(5):1277-82. doi: 10.1002/ijc.25766. Epub 2011 Feb 26.

Abstract

Target-specific acute myeloid leukemia (AML) immunotherapy requires selective cell-surface antigens on AML blast cells. CD64 is a promising candidate antigen because it is abundantly expressed on monocytoid differentiated AML subtypes. In previous studies, a chemically linked full-length anti-CD64 immunotoxin based on ricin A showed promising results in several animal models, but further development has been hindered by its substantial, dose-limiting off-target effects. We recently constructed the recombinant immunotoxin H22(scFv)-ETA', comprising a truncated Pseudomonas exotoxin A (PE) and a humanized scFv antibody against CD64. This molecule was shown to kill CD64(+) AML-derived tumor cell lines and primary patient-derived AML cells specifically, both in vitro and ex vivo. Here we describe the in vivo efficiency of H22(scFv)-ETA' in the U937/SCID mouse xenograft model for human AML, by providing immunohistochemical evidence for the elimination of human CD64(+) tumor cells in mouse organs. H22(scFv)-ETA' showed potent antitumor activity against myeloid tumor cells and significantly prolonged the overall survival of AML xenograft animals. In conclusion, H22(scFv)-ETA' is efficacious against AML with monocytoid differentiation in vitro and in animal models in vivo, providing the basis for a novel therapeutic strategy for the treatment of AML patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / genetics
  • ADP Ribose Transferases / immunology*
  • Animals
  • Bacterial Toxins / genetics
  • Bacterial Toxins / immunology*
  • Disease Models, Animal*
  • Exotoxins / genetics
  • Exotoxins / immunology*
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Immunoglobulin Variable Region / genetics
  • Immunoglobulin Variable Region / immunology
  • Immunotoxins / genetics
  • Immunotoxins / immunology*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / immunology
  • Leukemia, Myeloid, Acute / therapy*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Pseudomonas aeruginosa Exotoxin A
  • Receptors, IgG / genetics
  • Receptors, IgG / immunology
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / therapeutic use*
  • Single-Chain Antibodies / genetics
  • Single-Chain Antibodies / immunology*
  • Survival Rate
  • Tumor Cells, Cultured
  • Virulence Factors / genetics
  • Virulence Factors / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • Bacterial Toxins
  • Exotoxins
  • Immunoglobulin Variable Region
  • Immunotoxins
  • Receptors, IgG
  • Recombinant Fusion Proteins
  • Single-Chain Antibodies
  • Virulence Factors
  • ADP Ribose Transferases