Inhibitory anti-FLT3 antibodies are capable of mediating antibody-dependent cell-mediated cytotoxicity and reducing engraftment of acute myelogenous leukemia blasts in nonobese diabetic/severe combined immunodeficient mice.
Aberrant FLT3 expression and/or mutation plays a significant role in leukemogenesis. This has prompted the development of selective small molecule tyrosine kinase inhibitors against FLT3. However, like most tyrosine kinase inhibitors, those against FLT3 are not completely specific and at the doses required to completely inhibit target, significant toxicities may occur. In addition, tyrosine kinase inhibitors for other kinases have been shown to select for cells that become resistant. To overcome some of these limitations we developed two fully human phage display monoclonal antibodies against FLT3 (IMC-EB10 and IMC-NC7). These antibodies inhibited ligand-mediated activation of wild-type FLT3 and constitutively activated mutant FLT3 and in most cell types affected downstream STAT5, AKT, and mitogen-activated protein kinase activation. In addition to interfering with FLT3 signaling, IMC-EB10 and, to a significantly lesser extent, IMC-NC7 initiated antibody-dependent cell-mediated cytotoxicity on FLT3-expressing cells. When IMC-EB10 was used in vivo to treat nonobese diabetic/severe combined immunodeficient mice given injections of primary FLT3/ITD acute myelogenous leukemia samples or myeloid cell lines with FLT3 expression, it significantly decreased engraftment of leukemic cells and increased survival, respectively. In contrast, IMC-EB10 treatment did not reduce engraftment of normal human CD34+ cord blood cells nor did it show any significant inhibition of normal murine hematopoiesis. Thus, these types of antibodies have the potential to be safe and effective new therapeutic agents for acute myelogenous leukemia and possibly other FLT3-expressing malignancies.
Piloto
Obdulio
O
Department of Oncology and Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. opiloto1@jhmi.edu
Levis
Mark
M
Huso
David
D
Li
Yiwen
Y
Li
Hongli
H
Wang
Mei-Nai
MN
Bassi
Rajiv
R
Balderes
Paul
P
Ludwig
Dale L
DL
Witte
Larry
L
Zhu
Zhenping
Z
Hicklin
Daniel J
DJ
Small
Donald
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051941:fms-Like Tyrosine Kinase 3
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3