Development of a fully human anti-PDGFRbeta antibody that suppresses growth of human tumor xenografts and enhances antitumor activity of an anti-VEGFR2 antibody.
Platelet-derived growth factor receptor beta (PDGFRbeta) is upregulated in most of solid tumors. It is expressed by pericytes/smooth muscle cells, fibroblast, macrophage, and certain tumor cells. Several PDGF receptor-related antagonists are being developed as potential antitumor agents and have demonstrated promising antitumor activity in both preclinical and clinical settings. Here, we produced a fully human neutralizing antibody, IMC-2C5, directed against PDGFRbeta from an antibody phage display library. IMC-2C5 binds to both human and mouse PDGFRbeta and blocks PDGF-B from binding to the receptor. IMC-2C5 also blocks ligand-stimulated activation of PDGFRbeta and downstream signaling molecules in tumor cells. In animal studies, IMC-2C5 significantly delayed the growth of OVCAR-8 and NCI-H460 human tumor xenografts in nude mice but failed to show antitumor activities in OVCAR-5 and Caki-1 xenografts. Our results indicate that the antitumor efficacy of IMC-2C5 is primarily due to its effects on tumor stroma, rather than on tumor cells directly. Combination of IMC-2C5 and DC101, an anti-mouse vascular endothelial growth factor receptor 2 antibody, resulted in significantly enhanced antitumor activity in BxPC-3, NCI-H460, and HCT-116 xenografts, compared with DC101 alone, and the trend of additive effects to DC101 treatment in several other tumor models. ELISA analysis of NCI-H460 tumor homogenates showed that IMC-2C5 attenuated protein level of vascular endothelial growth factor and basic fibroblast growth factor elevated by DC101 treatment. Finally, IMC-2C5 showed a trend of additive effects when combined with DC101/chemotherapy in MIA-PaCa-2 and NCI-H460 models. Taken together, these results lend great support to the use of PDGFRbeta antagonists in combination with other antiangiogenic agents in the treatment of a broad range of human cancers.
Shen
Juqun
J
ImClone Systems, New York, NY 10014, USA. juqun.shen@imclone.com
Vil
Marie Danielle
MD
Prewett
Marie
M
Damoci
Chris
C
Zhang
Haifan
H
Li
Huiling
H
Jimenez
Xenia
X
Deevi
Dhanvanthri S
DS
Iacolina
Michelle
M
Kayas
Anthony
A
Bassi
Rajiv
R
Persaud
Kris
K
Rohoza-Asandi
Anna
A
Balderes
Paul
P
Loizos
Nick
N
Ludwig
Dale L
DL
Tonra
James
J
Witte
Larry
L
Zhu
Zhenping
Z
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D000915:Antibody Affinity / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019151:Peptide Library; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000276:immunology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C511761:DC101 monoclonal antibody; D019151:Peptide Library; D020797:Receptor, Platelet-Derived Growth Factor beta