title: In vivo efficacy of the recombinant anti-CD64 immunotoxin H22(scFv)-ETA' in a human acute myeloid leukemia xenograft tumor model.
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.
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, Helmholtz-Institute for Biomedical Engineering, University Hospital RWTH Aachen, Aachen, Germany. tur@hia.rwth-aachen.de
authors.forename: Mehmet Kemal
authors.initials: MK
authors.lastname: Tur
authors.forename: Michael
authors.initials: M
authors.lastname: Huhn
authors.forename: Edgar
authors.initials: E
authors.lastname: Jost
authors.forename: Theo
authors.initials: T
authors.lastname: Thepen
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.forename: Stefan
authors.initials: S
authors.lastname: Barth
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005098:Exotoxins / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D000922:Immunotoxins / Q000235:genetics / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use*; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D007135:Immunoglobulin Variable Region; D000922:Immunotoxins; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A