title: An antibody directed against PDGF receptor beta enhances the antitumor and the anti-angiogenic activities of an anti-VEGF receptor 2 antibody.
abstract: 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.
authors.affiliation: ImClone Systems Incorporated, New York, NY 10014, USA. juqun.shen@imclone.com
authors.forename: Juqun
authors.initials: J
authors.lastname: Shen
authors.forename: Marie D
authors.initials: MD
authors.lastname: Vil
authors.forename: Haifan
authors.initials: H
authors.lastname: Zhang
authors.forename: James R
authors.initials: JR
authors.lastname: Tonra
authors.forename: Ling L
authors.initials: LL
authors.lastname: Rong
authors.forename: Chris
authors.initials: C
authors.lastname: Damoci
authors.forename: Marie
authors.initials: M
authors.lastname: Prewett
authors.forename: Dhanvanthri S
authors.initials: DS
authors.lastname: Deevi
authors.forename: Jessica
authors.initials: J
authors.lastname: Kearney
authors.forename: David
authors.initials: D
authors.lastname: Surguladze
authors.forename: Xenia
authors.initials: X
authors.lastname: Jimenez
authors.forename: Michelle
authors.initials: M
authors.lastname: Iacolina
authors.forename: Rajiv
authors.initials: R
authors.lastname: Bassi
authors.forename: Kai
authors.initials: K
authors.lastname: Zhou
authors.forename: Paul
authors.initials: P
authors.lastname: Balderes
authors.forename: Venkat R M
authors.initials: VR
authors.lastname: Mangalampalli
authors.forename: Nick
authors.initials: N
authors.lastname: Loizos
authors.forename: Dale L
authors.initials: DL
authors.lastname: Ludwig
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
mesh_terms: 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*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2