Abstract
Anti-vascular endothelial growth factor (VEGF) therapies have improved clinical outcomes for patients with cancers and retinal vascular diseases. Three anti-VEGF agents, pegaptanib, ranibizumab, and aflibercept, are approved for ophthalmic indications, while bevacizumab is approved to treat colorectal, lung, and renal cancers, but is also used off-label to treat ocular vascular diseases. The efficacy of bevacizumab relative to ranibizumab in treating neovascular age-related macular degeneration has been assessed in several trials. However, questions persist regarding its safety, as bevacizumab can form large complexes with dimeric VEGF165, resulting in multimerization of the Fc domain and platelet activation. Here, we compare binding stoichiometry, Fcγ receptor affinity, platelet activation, and binding to epithelial and endothelial cells in vitro for bevacizumab and aflibercept, in the absence or presence of VEGF. In contrast to bevacizumab, aflibercept forms a homogenous 1:1 complex with each VEGF dimer. Unlike multimeric bevacizumab:VEGF complexes, the monomeric aflibercept:VEGF complex does not exhibit increased affinity for low-affinity Fcγ receptors, does not activate platelets, nor does it bind to the surface of epithelial or endothelial cells to a greater degree than unbound aflibercept or control Fc. The latter finding reflects the fact that aflibercept binds VEGF in a unique manner, distinct from antibodies not only blocking the amino acids necessary for VEGFR1/R2 binding but also occluding the heparin-binding site on VEGF165.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-016-9515-8) contains supplementary material, which is available to authorized users.
Highlights
Angiogenesis, the growth of new blood vessels from preexisting vasculature, is a highly orchestrated process that is critical for proper embryonic and postnatal vascular development [1]
Additional studies have provided evidence that bevacizumab binds cellsurface-bound vascular endothelial growth factor (VEGF) on retinal pigment epithelium (RPE) cells, but that this binding may trigger the complement cascade resulting in cell death [3, 33]
To further understand what could be driving these observed differences in vitro, we conducted a detailed analysis of bevacizumab and aflibercept when complexed with VEGF by analyzing their stoichiometry of binding, affinity to Fcc receptors, propensity to activate platelets and ability to bind ARPE-19 and human umbilical vein endothelial cells (HUVEC)
Summary
Angiogenesis, the growth of new blood vessels from preexisting vasculature, is a highly orchestrated process that is critical for proper embryonic and postnatal vascular development [1]. Abnormal or pathological angiogenesis is a hallmark of cancer and several retinal diseases where the upregulation of proangiogenic factors, such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), leads to increases in endothelial proliferation, changes in vasculature morphology, and increased vascular permeability [2, 3]. Blockade of VEGF has shown clinical utility in the oncology setting as well as several retinal vascular diseases characterized by abnormal angiogenesis and/or vascular permeability, such as the ‘‘wet’’ form of age-related macular degeneration (AMD), the leading cause of blindness in the elderly [4, 5]. Blocking VEGF activity has become the therapy of choice for treating diabetic macular edema (DME), retinal vein occlusions, and other ocular diseases where abnormal angiogenesis is the underlying etiology [7,8,9,10]
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