title: The Fc-alpha receptor is a new target antigen for immunotherapy of myeloid leukemia.
abstract: Antibody-based immunotherapy of leukemia requires the targeting of specific antigens on the surface of blasts. The Fc gamma receptor (CD64) has been investigated in detail, and CD64-targeting immunotherapy has shown promising efficacy in the targeted ablation of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML) and chronic myeloid leukemia cells (CML). Here we investigate for the first time the potential of FcαRI (CD89) as a new target antigen expressed by different myeloid leukemic cell populations. For specific targeting and killing, we generated a recombinant fusion protein comprising an anti-human CD89 single-chain Fragment variable and the well-characterized truncated version of the potent Pseudomonas aeruginosa exotoxin A (ETA'). Our novel therapeutic approach achieved in vitro EC50 values in range 0.2-3 nM depending on the applied stimuli, that is, interferon gamma or tumor necrosis factor alpha. We also observed a dose-dependent apoptosis-mediated cytotoxicity, which resulted in the elimination of up to 90% of the target cells within 72 hr. These findings were also confirmed ex vivo using leukemic primary cells from peripheral blood samples of three previously untreated patients. We conclude that CD89-specific targeting of leukemia cell lines can be achieved in vitro and that the efficient elimination of leukemic primary cells supports the potential of CD89-ETA' as a potent, novel immunotherapeutic agent.
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.|Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology, Aachen, Germany.
authors.forename: Radoslav
authors.initials: R
authors.lastname: Mladenov
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.|Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology, Aachen, Germany.
authors.forename: Dmitrij
authors.initials: D
authors.lastname: Hristodorov
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Cremer
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Hein
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kreutzer
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Stroisch
authors.affiliation: Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology, Aachen, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Niesen
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Brehm
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Blume
authors.affiliation: Department of Hematology and Oncology (Internal Medicine IV), RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Tim Henrik
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Department of Hematology and Oncology (Internal Medicine IV), RWTH Aachen University Hospital, Aachen, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Jost
authors.affiliation: Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology, Aachen, Germany.
authors.forename: Theophilus
authors.initials: T
authors.lastname: Thepen
authors.affiliation: Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology, Aachen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Department of Internal Medicine 5 Hematology/Oncology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Stockmeyer
authors.affiliation: Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Stefan
authors.initials: S
authors.lastname: Barth
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.|Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology, Aachen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Stein
mesh_terms: D036002:ADP Ribose Transferases / Q000276:immunology; D000368:Aged; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology; D005098:Exotoxins / Q000276:immunology; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D007951:Leukemia, Myeloid / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011961:Receptors, Fc / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D020298:U937 Cells; D037521:Virulence Factors / Q000276:immunology; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D001427:Bacterial Toxins; D005098:Exotoxins; D007371:Interferon-gamma; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C036832:Fc(alpha) receptor
keywords: ETA'; FcαR; immunotherapy; immunotoxin; myeloid leukemia