Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy

• Published in: Cancer and metastasis reviews 1998-06, Vol.17 (2), p.155-161
• Main Authors: Witte, L, Hicklin, D J, Zhu, Z, Pytowski, B, Kotanides, H, Rockwell, P, Böhlen, P
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Humans; Mice; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - drug therapy; Neovascularization, Pathologic - immunology; Neovascularization, Pathologic - prevention & control; Rats; Receptor Protein-Tyrosine Kinases - immunology; Receptors, Growth Factor - immunology; Receptors, Mitogen - immunology; Receptors, Vascular Endothelial Growth Factor; Signal Transduction - drug effects
• ISSN: 0167-7659; 1573-7233
• DOI: 10.1023/a:1006094117427

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.