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The Fc‐alpha receptor is a new target antigen for immunotherapy of myeloid leukemia
Author(s) -
Mladenov Radoslav,
Hristodorov Dmitrij,
Cremer Christian,
Hein Lea,
Kreutzer Fabian,
Stroisch Tim,
Niesen Judith,
Brehm Hannes,
Blume Tobias,
Brümmendorf Tim Henrik,
Jost Edgar,
Thepen Theophilus,
Fischer Rainer,
Stockmeyer Bernhard,
Barth Stefan,
Stein Christoph
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29628
Subject(s) - myeloid leukemia , immunotherapy , acute myelomonocytic leukemia , antigen , leukemia , immunology , myeloid , cancer research , immunotoxin , pseudomonas exotoxin , medicine , antibody , biology , in vitro , cytotoxicity , immune system , monoclonal antibody , biochemistry
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 EC 50 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.