An Antibody Directed Against Pdgf Receptor Beta Enhances The Antitumor And The Anti-Angiogenic Activities Of An Anti-Vegf Receptor 2 Antibody

Platelet-derived growth factor (PDGF) and its receptors (PDGFR) play important roles in tumorigenesis through stimulating tumor growth and promoting angiogenesis via enhancing pericyte recruitment and vessel maturation. Here we produced a neutralizing antibody, IB3, directed against mouse PDGFR beta. IB3 binds to PDGFR beta with high affinity (9 x 10(-11) M) and blocks PDGF-BB from binding to the receptor with an IC50 of similar to 1.2 nM. The antibody also blocks ligand-stimulated activation of PDGFR beta and downstream signaling molecules, including Akt and MAPK p42/44, in tumor cells. In animal studies, IB3 significantly enhanced the antitumor and the anti-angiogenic activities of DC101, an antibody directed against mouse vascular endothelial growth factor receptor 2, in a pancreatic (BxPC-3) and a non-small cell lung (NCI-H460) tumor xenograft models. Treatment with the combination of IB3 and DC101 in BxPC-3 xenograft-bearing mice resulted in tumor regression in 58% of mice compared to that in 18% of mice treated with DC101 alone. Taken together, these results lend great support to use PDGFR beta antagonists in combinations with other antitumor and/or anti-angiogenic agents in the treatment of a variety of cancers. (c) 2007 Elsevier Inc. All rights reserved.