542

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 (1B3) directed against mouse PDGFRβ from an antibody phage display library. 1B3 binds to PDGFRβ with high affinity (4.2 x 10-11M), and blocks PGDF-BB from binding to the receptor with an IC50 of ∼ 1.2 nM. The antibody also blocked ligand-stimulated activation of PDGFRβ and downstream signaling molecules, including Akt and MAPK p42/44, in tumor cells. Further, 1B3 significantly inhibited the growth of SK-OV-3 human ovarian carcinoma xenografts in nude mice when administered by intraperitonal injections at 60 mg/kg twice a week. Immunohistochemistry study on day 54 post the start of the treatment revealed significantly reduced cellularity in tumors treated with 1B3 compared to those treated with a control IgG. 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. 1B3 antibody provides an excellent reagent for investigating the antitumor activity and potential toxicities associated with specific anti-PDGFRβ therapy.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]