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Departments of 1 Antibody Technology, 2 Molecular and Cell Biology, and 3 Protein Science, ImClone Systems Incorporated, New York, New York
Requests for reprints: Zhenping Zhu, Department of Antibody Technology, ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014. Phone: 646-638-5190; Fax: 212-645-2054. E-mail: zhenping{at}imclone.com
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.
Key Words: Angiogenesis • Lymphangiogenesis • VEGFR2/KDR • VEGFR3/Flt-4 • Bispecific antibody • Diabody • Antibody engineering • Human antibody • Dual blocking
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: X. Jimenez and D. Lu contributed equally to this study.
Received 9/24/04; revised 1/18/05; accepted 1/25/05.
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