Anti-FLT3 immunotherapy for the treatment of acute leukemias

For a large number of patients, acute leukemia remain an incurable disease that often carries a death sentence. Novel therapeutic strategies are clearly needed if we are to improve patient survival. FMS-like tyrosine kinase 3 (FLT3) is an attractive receptor for molecularly targeted therapy due to its expression on cells in most cases of acute leukemias and its roles in leukemogenesis. Studies were performed to investigate the therapeutic potential of anti-FLT3 immunotherapy for the possible treatment of acute leukemias. In contrast to small molecule inhibitors, antibodies are more specific and therefore less toxic and have the added advantage of recruiting the host's immune system against the targeted cells. EB10 and NC7 are two fully human anti-FLT3 monoclonal antibodies that resulted from a screen performed in collaboration with ImClone Systems Inc. These mAbs affect FLT3 phosphorylation and downstream signaling pathways in various FLT3-expressing leukemic cells. Murine xenograph studies using leukemic cell lines and patient samples demonstrate that EB10 treatment can reduce leukemic engraftment, often below 0.001% human cells, and prolongs survival without affecting the engraftment of normal hematopoietic stem cells. Anti-FLT3 immunotherapy even proved efficacious against FLT3 inhibitor resistant leukemic cell lines that activate compensatory signaling pathways as the mode of resistance to FLT3 inhibitors. Mechanistic studies revealed that the in vivo activity of EB10 is mediated through antibody dependent cell-mediated cytotoxicity and involves natural killer cells, which can be activated to improve the in vivo efficacy of EB10. These data suggest that anti-FLT3 immunotherapy is an effective and safe therapeutic strategy for the possible treatment of acute leukemias.