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Vascular Endothelial Growth Factor Receptor Antibodies for Anti-Angiogenic Therapy

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Tumor Angiogenesis

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Abstract

Vascular endothelial cell growth factors (VEGFs) and their receptors are key molecules in the development and maintenance of the vascular and lymphatic systems in mammals. Inappropriate regulation of vascular growth is associated with various pathological states, especially with tumor growth. As cancer growth is supported in large part by excessive tumor-induced vascularization, interference with VEGF signaling has emerged as an important anti-angiogenic strategy to combat cancer. Here we review the state of the art with regard to one powerful such approach — the efficient blockage of VEGF receptor function with fully human monoclonal antibodies. There are three types of VEGF receptors: VEGFR2 and VEGFR3, which are expressed highly selectively on vascular and lymphatic endothelial cells, respectively, and VEGFR1, which is expressed in many cell types, including endothelial cells, inflammatory cells, and many tumor cells. Antibodies against each of these receptors can interfere with VEGF/VEGF receptor interactions in a highly receptor-specific manner, which prevents VEGF-induced signaling in VEGF receptor-positive cells, and results in impairment of essential functions of endothelial and other cells that support tumor growth and, ultimately, by tumor growth inhibition. The mechanisms of action of these antibodies differ widely, reflecting the unique distribution and biological roles of each of the VEGF receptors. There is abundant preclinical evidence that antibody-mediated VEGF receptor blockage can cause powerful inhibition of tumor growth in animals. However, as tumor growth control is achieved by mechanisms that are primarily cytostatic, cessation of treatment causes tumor re-growth. A preferred treatment modality is, therefore, to combine antibody treatment with cytotoxic (chemo- or radiation) therapy. Various forms of such combination therapy have been successful in treating many types of experimental tumors, even under conditions when single-agent treatments are ineffective. Anti-VEGFR1 and -R2 antibodies are currently being investigated as cancer therapeutics in clinical trials. In view of the potential therapeutic usefulness of these antibodies we also discuss possible advantages and disadvantages of anti-VEGFR antibodies and other approaches of VEGF signaling inhibition [antibodies against VEGF (Avastin®), small-molecule kinase inhibitors] with respect to differential efficacy and adverse effect profiles.

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  1. 2237 Cortina Circle, Escondido, CA, 92029, USA

    Dr. Peter Bohlen

  2. ImClone Systems, 180 Varick Street, New York, NY, 10014, USA

    Zhenping Zhu & Daniel J. Hicklin

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  1. Klinik fĂĽr Tumorbiologie, Breisacher Str. 117, 79106, Freiburg i. Br., Germany

    Dieter Marmé PhD (Professor) (Professor)

  2. DKFZ, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Norbert Fusenig MD (Professor, former Head of Division of Carcinogenesis and Differentiation) (Professor, former Head of Division of Carcinogenesis and Differentiation)

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Bohlen, P., Zhu, Z., Hicklin, D.J. (2008). Vascular Endothelial Growth Factor Receptor Antibodies for Anti-Angiogenic Therapy. In: Marmé, D., Fusenig, N. (eds) Tumor Angiogenesis. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-33177-3_24

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