Abstract
Biological evidence suggests that interference with the function of the angiogenic growth factor receptor VEGFR2 (flk1/KDR) is a particularly promising strategy to inhibit tumor-induced angiogenesis. Proof of concept was established by developing a monoclonal rat anti-mouse VEGFR2 antibody (DC101) and showing that it potently blocked the binding of VEGF to its receptor, inhibited VEGF-induced signaling, and strongly blocked tumor growth in mice through an anti-angiogenic mechanism. Since DC101 does not cross-react with the human VEGFR2 KDR, anti-KDR monoclonal antibodies were generated by standard hybridoma technology and by using phage display library. High affinity antibodies (Kd = 4.9 × 1010−10 − 1.1 × 1010 9 M) were found with both approaches. The anti-KDR antibodies compete on an equimolar basis with VEGF for binding to KDR and inhibit with similar potency the VEGF-induced signaling and mitogenesis in human endothelial cells. Although these antibodies cannot be tested for in vivo efficacy in standard murine tumor models because of lack of species cross-reactivity, the similarity of their in vitro properties with those of DC101 suggests that they may be effective in blocking KDR function in vivo.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27-31, 1995
Gradishar W: An overview of clinical trials involving inhibitors of angiogenesis and their mechanism of action. Invest New Drugs 15: 49-59, 1997
Dvorak HF, Detmar M, Claffey KP, Nagy JA, Vandewater L, Senger DR: Vascular permeability factor vascular endothelial growth factor—an important mediator of angiogenesis in malignancy and inflammation. Int Arch Allergy Immunol 107: 233-235, 1995
Ferrara N: The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 36: 127-137, 1995
Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843-845, 1992
Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declereq C, Pawling J, Moons L, Collen D, Risan W, Nagy A: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435-439, 1996
Zhang HT, Craft P, Scott PAE, Ziche M, Weich HA, Harris AL, Bicknell R: Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J Nat Cancer Inst 87: 213-219, 1995
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362: 841-844, 1993
Saleh M, Stacker SA, Wilks AF: Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res 56: 393-401, 1996
Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LEH: Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA 92: 10457-10461, 1995
Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC: Failure of blood island development and vasculogenesis in flk-1-deficient mice. Nature 376: 62-66, 1995
Lindner V, Reidy MA: Expression of VEGF receptors in arteries after endothelial injury and lack of increased endothelial regrowth in response to VEGF. Arterioscler Thromb Vasc Biol 16: 1399-1405, 1996
Plate KH, Breier G, Weich HA, Mennel HD, Risau W: Vascular endothelial growth factor and glioma angiogenesis. Coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer 59: 520-529, 1994
Millauer B, Longhi MP, Plate KH, Shawver LK, Risau W, Ullrich A, Strawn LM: Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res 56: 1615-1620, 1996
Rockwell P, Goldstein N: Role of protein tyrosine kinase receptors in cancer Possibilities for therapeutic intervention Mol Cell Diff 3: 315-335, 1995
Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE: Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 3: 1222-1227, 1997
Rockwell P, Neufeld G, Glassman A, Caron D, Goldstein N: In vitro neutralization of vascular endothelial growth factor activation of Flk-1 by a monoclonal antibody. Mol Cell Diff 3: 91-109, 1995
Flanagan JG, Leder P: The kit ligand: A cell surface molecule altered in steel mutant fibroblasts. Cell 63: 185-194, 1990
Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin C-H: Different signal transduction properties of KDR and fltl, two receptors for vascular endothelial growth factor. J Biol Chem 269: 26988-26995, 1994
Juhasz I, Albelda SM, Elder DE, Murphy GF, Adachi K, Herlyn D, Valyi Nagy IT, Herlyn M: Growth and invasion of human melanomas in human skin grafted to immunodeficient mice. Am J Pathol 143: 528-537, 1993
McLeod DS, Crone SN, Lutty GA: Vasoproliferation in the neonatal dog model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 37: 1322-1333, 1996
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Witte, L., Hicklin, D.J., Zhu, Z. et al. Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev 17, 155–161 (1998). https://doi.org/10.1023/A:1006094117427
Issue Date:
DOI: https://doi.org/10.1023/A:1006094117427