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Blood, 15 August 2004, Vol. 104, No. 4, pp. 1137-1144.
Prepublished online as a Blood First Edition Paper on April 22, 2004; DOI 10.1182/blood-2003-07-2585.
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Submitted July 30, 2003
Accepted April 8, 2004
Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibody
Yiwen Li*, Hongli Li, Mei-Nai Wang, Dan Lu, Rajiv Bassi, Yan Wu, Haifan Zhang, Paul Balderes, Dale L Ludwig, Bronislaw Pytowski, Paul Kussie, Obdulio Piloto, Donald Small, Peter Bohlen, Larry Witte, Zhenping Zhu, and Daniel J Hicklin
ImClone Systems Incorporated, New York, NY, USA
Oncology, Jonhs Hopkins School of Medicine, Baltimore, MD, USA
* Corresponding author; email: Yiwen.Li{at}imclone.com.
FLT3, a Class III receptor tyrosine kinase, is expressed at high levels in blasts of ~90% of acute myelogenous leukemia (AML) patients. Internal tandem duplications (ITDs) in the juxtamembrane portion and point mutations in the kinase domain of FLT3 are found in ~37% of AML patients and are associated with a poor prognosis. We report here the development and characterization of a fully human anti-FLT3 neutralizing antibody (IMC-EB10) isolated from a human Fab phage display library. IMC-EB10 (IgG1,  ) binds with high affinity (KD = 158 pM) to soluble FLT3 in ELISA and to FLT3 receptor expressed on the surface of human leukemia cell lines. IMC-EB10 blocks the binding of FLT3 ligand (FL) to soluble FLT3 in ELISA and competes with FL for binding to cell surface FLT3 receptor. IMC-EB10 treatment inhibits FL-induced phosphorylation of FLT3 in EOL-1 and EM3 leukemia cells and FL-independent constitutive activation of ITD-mutant FLT3 in BaF3-ITD and MV4;11 cells. The activation of downstream signaling proteins MAPK and AKT is also inhibited in these cell lines by antibody treatment. The antibody inhibits FL-stimulated proliferation of EOL-1 cells as well as ligand-independent proliferation of BaF3-ITD cells. In both EOL-1 xenograft and BaF3-ITD leukemia models, treatment with IMC-EB10 significantly prolongs the survival of leukemia-bearing mice. No overt toxicity is observed with IMC-EB10 treatment. Taken together, these data demonstrate that IMC-EB10 is a specific and potent inhibitor of both wild-type and ITD-mutant FLT3, and deserves further study for targeted therapy of human AML.
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