Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy.
Biological evidence suggests that interference with the function of the angiogenic growth factor receptor VEGFR2 (flk1/KDR) is a particularly promising strategy to inhibit tumor-induced angiogenesis. Proof of concept was established by developing a monoclonal rat anti-mouse VEGFR2 antibody (DC101) and showing that it potently blocked the binding of VEGF to its receptor, inhibited VEGF-induced signaling, and strongly blocked tumor growth in mice through an anti-angiogenic mechanism. Since DC101 does not cross-react with the human VEGFR2 KDR, anti-KDR monoclonal antibodies were generated by standard hybridoma technology and by using phage display library. High affinity antibodies (Kd = 4.9 x 10(-10)-1.1 x 10(-9) M) were found with both approaches. The anti-KDR antibodies compete on an equimolar basis with VEGF for binding to KDR and inhibit with similar potency the VEGF-induced signaling and mitogenesis in human endothelial cells. Although these antibodies cannot be tested for in vivo efficacy in standard murine tumor models because of lack of species cross-reactivity, the similarity of their in vitro properties with those of DC101 suggests that they may be effective in blocking KDR function in vivo.
Witte
L
L
Department of Molecular and Cell Biology, ImClone Systems Incorporated, New York, USA. larryw@imclone.com
Hicklin
D J
DJ
Zhu
Z
Z
Pytowski
B
B
Kotanides
H
H
Rockwell
P
P
Böhlen
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D017978:Receptors, Growth Factor / Q000276:immunology*; D011975:Receptors, Mitogen / Q000276:immunology; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D017978:Receptors, Growth Factor; D011975:Receptors, Mitogen; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor