4790

Platelet-derived growth factor (PDGF) and its receptors (PDGFR) play important roles in tumorigenesis through both directly stimulating tumor growth and promoting pericyte recruitment and vessel maturation during angiogenesis. Several PDGF receptor antagonists are being developed as potential antitumor agents, and have demonstrated promising antitumor activity in both preclinical and clinical settings. Here we isolated a neutralizing antibody (2C5) directed against human PDGFRβ from an antibody phage display library. 2C5 binds to human PDGFRβ with high affinity (1.36 x 10-11M), and it also cross-reacts with mouse PDGFRβ (6.05 x 10-11M). 2C5 blocks PDGF-BB from binding to the receptor with an IC50 of 0.55 nM for the human receptor and 0.35 nM for the mouse receptor. The antibody also blocked ligand-stimulated activation of PDGFRβ and downstream signaling molecules, including Akt and MAPK p42/44, in both human and mouse tumor cells. Further, 2C5 significantly inhibited the growth of OVCAR-8 human ovarian carcinoma xenografts and NCI-H460 human NSCLC xenografts in nude mice when administered by intraperitonal injections at 60mg/kg twice a week or 40 mg/kg three times a week. Further, 2C5 significantly enhanced the antitumor activity of DC101, an antibody directed against mouse vascular endothelial growth factor receptor 2, in BxPC-3 model. No apparent treatment-related toxicities, such as body weight changes and physical signs of illness, were observed in mice treated for up to 8 weeks. 2C5 antibody provides an excellent reagent for investigating the antitumor activity in animal study and has a potential to be developed as an anti-cancer drug and/or an enhancer of other targeted therapy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA