This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, Y. Articles by Hicklin, D. J. Search for Related Content PubMed PubMed Citation Articles by Wu, Y. Articles by Hicklin, D. J.

Anti-Vascular Endothelial Growth Factor Receptor-1 Antagonist Antibody as a Therapeutic Agent for Cancer

Authors' Affiliations: Departments of ¹ Experimental Therapeutics, ² Protein Sciences, ³ Antibody Technology, and ⁴ Cell Engineering and Expression, ImClone Systems, Inc., New York, New York

Requests for reprints: Yan Wu, Department of Experimental Therapeutics, ImClone Systems, Inc., 180 Varick Street, New York, NY 10014. Phone: 212-645-1405; Fax: 212-645-2054; E-mail: Yan.Wu{at}imclone.com.

Purpose: Vascular endothelial growth factor receptor-1 (VEGFR-1) plays important roles in promotion of tumor growth by mediating cellular functions in tumor vascular endothelium and cancer cells. Blockade of VEGFR-1 activation has been shown to inhibit pathologic angiogenesis and tumor growth, implicating VEGFR-1 as a potential therapeutic target for the treatment of cancer. We have thus developed a VEGFR-1 antagonist human monoclonal antibody designated as IMC-18F1 and evaluated its antitumor activity in preclinical experimental models to show the therapeutic potential of the antibody for cancer treatment in clinic.

Experimental Design: Human IgG transgenic mice were used for generation of anti-VEGFR-1 antibodies. Anti-VEGFR-1-specific blocking antibodies were identified using solid-phase binding and blocking assays. Inhibitory antitumor cell activity of IMC-18F1 was assessed in cell-based kinase and growth assays. Pharmacokinetic/pharmacodynamic studies were done to determine the association of antibody blood level with antitumor efficacy of the antibody in vivo. Antitumor efficacy of the anti-VEGFR-1 antibodies as monotherapy and in combination with cytotoxic agents was evaluated in human breast cancer xenograft models.

Results: A fully human neutralizing antibody, IMC-18F1, was shown to be a high-affinity (K_D = 54 pmol) inhibitor of VEGFR-1 ligand binding (VEGF-A, VEGF-B, and placental growth factor). IMC-18F1 inhibited ligand-induced intracellular activation of VEGFR-1 and mitogen-activated protein kinase signaling and prevented ligand-stimulated in vitro growth of breast cancer cells. In vivo, IMC-18F1 suppressed the growth of human breast tumor xenografts in association with reduced mitogen-activated protein kinase and Akt activation, reduced tumor cell proliferation, and increased tumor cell apoptosis. Pharmacokinetic/pharmacodynamic studies established a plasma elimination half-life of 5 days for IMC-18F1 and a steady-state trough plasma therapeutic threshold of 88 µg/mL. Importantly, inhibition of mouse and human VEGFR-1 with MF1 and IMC-18F1, respectively, enhanced the antitumor efficacy of cytotoxic agents commonly used to treat breast cancer.

Conclusions: Based on preclinical validation studies, IMC-18F1 anti-VEGFR-1 has potential to provide clinical benefit to cancer patients.

This article has been cited by other articles:

				A. Coxon, T. Bush, D. Saffran, S. Kaufman, B. Belmontes, K. Rex, P. Hughes, S. Caenepeel, J. B. Rottman, A. Tasker, et al. Broad Antitumor Activity in Breast Cancer Xenografts by Motesanib, a Highly Selective, Oral Inhibitor of Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor, and Kit Receptors Clin. Cancer Res., January 1, 2009; 15(1): 110 - 118. [Abstract] [Full Text] [PDF]

				S. Ponticelli, D. Marasco, V. Tarallo, R. J. C. Albuquerque, S. Mitola, A. Takeda, J.-M. Stassen, M. Presta, J. Ambati, M. Ruvo, et al. Modulation of Angiogenesis by a Tetrameric Tripeptide That Antagonizes Vascular Endothelial Growth Factor Receptor 1 J. Biol. Chem., December 5, 2008; 283(49): 34250 - 34259. [Abstract] [Full Text] [PDF]

				K. J. Till, R. J. Harris, A. Linford, D. G. Spiller, M. Zuzel, and J. C. Cawley Cell Motility in Chronic Lymphocytic Leukemia: Defective Rap1 and {alpha}L{beta}2 Activation by Chemokine Cancer Res., October 15, 2008; 68(20): 8429 - 8436. [Abstract] [Full Text] [PDF]

				Y. Lin, W. Li, K. Chen, and Y. Liu A Document Clustering and Ranking System for Exploring MEDLINE Citations J. Am. Med. Inform. Assoc., September 1, 2007; 14(5): 651 - 661. [Abstract] [Full Text] [PDF]