Suppression of leukemia growth in vivo by a novel anti-FLT3 antibody-auristatin conjugate
Cancer Research(2005)
Abstract
Proc Amer Assoc Cancer Res, Volume 46, 2005
6181
The class III receptor tyrosine kinase FLT3 is an attractive therapeutic target as it is overexpressed in blasts of ∼90% of acute myelogenous leukemia (AML) and the majority of B-lymphoid leukemia patients. Internal tandem duplications (ITDs) in the juxtamembrane region and point mutations in the kinase domain of FLT3 are found in ∼37% of AML patients and are associated with a poor prognosis. We have recently developed a fully human, high affinity monoclonal antibody (EB10) which is readily internalized upon binding to FLT3 receptor on human leukemia cells. In the present study, a novel auristatin conjugate of the anti-FLT3 antibody (EB10-MMAF) was prepared using a dipeptide linker that allows for drug release inside the lysosomes of antigen-positive cells. The MMAF conjugates were stable in buffers and plasma. EB10-MMAF (drug/antibody ratio = 8) retained the binding affinity and internalizing capability of EB10. The conjugate was highly potent, and selectively inhibited the growth of FLT3-expressing leukemia cells with an IC50 of 0.19 nM and 0.08 nM for MV4;11 and BaF3-ITD cells (both positive for FLT3-ITD), 1.11 nM, 6.18 nM and 1.82 nM for REH, EOL-1, EM3 cells (all three positive for wild-type FLT3), and 135 nM for JM1 (negative for FLT3). An MMAF conjugate with a control antibody was not active in these cell lines (IC50s > 5.9 uM). Flow cytometric analysis with annexin V indicated that EB10-MMAF treatment induced apoptosis of leukemia cells in vitro . In vivo treatment with EB10-MMAF strongly inhibited leukemia growth and prolonged survival of mice in both EOL-1 (mean survival time ∼81.0 +/− 46.8 days for the 3 mg/kg group compared to 41.5+/−15 days for the untreated group) and BaF3-ITD (mean survival time ∼91.5 +/− 39.5 days for the 5 mg/kg group compared to 32.8 +/− 5.2 days for the untreated group) leukemia models. In summary, immunoconjugates composed of a fully human anti-FLT3 antibody and a potent auristatin drug may provide a valuable therapeutic approach for AML and other FLT3-positive leukemias. In summary, immunoconjugates composed of a fully human anti-FLT3 antibody and a potent auristatin drug may provide a valuable therapeutic approach for AML and other types of FLT3-positive leukemia.
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Key words
leukemia growth,anti-flt,antibody-auristatin
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