A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3.
Vascular endothelial growth factors (VEGF) and their receptors (VEGFR) have been implicated to play important roles in tumor-associated angiogenesis and lymphangiogenesis, and hence in tumor growth and metastasis. We previously produced a number of fully human antibodies directed against VEGF receptor 2 (VEGFR2) and VEGF receptor 3 (VEGFR3) and showed that these antibodies are capable of inhibiting growth factor (VEGF and VEGF-C)-induced receptor activation, migration, and proliferation of human endothelial cells. In this report, we constructed and produced a bispecific antibody, a diabody, using the variable domain genes of two neutralizing antibodies, IMC-1121 to VEGFR2 and hF4-3C5 to VEGFR3. The diabody binds to both VEGFR2 and VEGFR3 in a dose-dependent manner, and blocks interaction between VEGF/VEGFR2, VEGF-C/VEGFR2, and VEGF-C/VEGFR3. In cell-based assays, the diabody neutralized both VEGF and VEGF-C-stimulated activation of VEGFR2, VEGFR3, and p44/p42 mitogen-activated protein kinase in endothelial cells. Furthermore, the diabody was able to inhibit both VEGF and VEGF-C-induced migration of endothelial cells. Taken together, our results suggest that a dual blockade of both VEGFR2 and VEGFR3 simultaneously may represent a more potent approach to effective cancer therapy.
Jimenez
Xenia
X
Department of Antibody Technology, ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA.
Lu
Dan
D
Brennan
Laura
L
Persaud
Kris
K
Liu
Meilin
M
Miao
Huaquan
H
Witte
Larry
L
Zhu
Zhenping
Z
D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry*; D001011:Aorta / Q000378:metabolism; D002417:Cattle; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry; D007167:Immunotherapy / Q000379:methods*; D007700:Kinetics; D020935:MAP Kinase Signaling System; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry* / Q000276:immunology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000737:chemistry* / Q000276:immunology
D018033:Antibodies, Bispecific; D007128:Immunoglobulin Fragments; D011994:Recombinant Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3