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, 1B3, directed against mouse PDGFRbeta. 1B3 binds to PDGFRbeta with high affinity (9x10(-11)M) and blocks PDGF-BB from binding to the receptor with an IC(50) of approximately 1.2 nM. The antibody also blocks ligand-stimulated activation of PDGFRbeta and downstream signaling molecules, including Akt and MAPK p42/44, in tumor cells. In animal studies, 1B3 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 1B3 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 PDGFRbeta antagonists in combinations with other antitumor and/or anti-angiogenic agents in the treatment of a variety of cancers.
Shen
Juqun
J
ImClone Systems Incorporated, New York, NY 10014, USA. juqun.shen@imclone.com
Vil
Marie D
MD
Zhang
Haifan
H
Tonra
James R
JR
Rong
Ling L
LL
Damoci
Chris
C
Prewett
Marie
M
Deevi
Dhanvanthri S
DS
Kearney
Jessica
J
Surguladze
David
D
Jimenez
Xenia
X
Iacolina
Michelle
M
Bassi
Rajiv
R
Zhou
Kai
K
Balderes
Paul
P
Mangalampalli
Venkat R M
VR
Loizos
Nick
N
Ludwig
Dale L
DL
Zhu
Zhenping
Z
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000276:immunology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2