Intracellular bevacizumab reduces phagocytotic uptake in RPE cells

Klettner, Alexa; Möhle, Friederike; Roider, Johann

doi:10.1007/s00417-010-1317-x

Cited by 46 publications

(43 citation statements)

References 25 publications

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“…Whether this finding has clinical significance remains uncertain. Furthermore, they also showed that bevacizumab affects the phagocytic ability of RPE cells more than ranibizumab does [22]. A similar inhibitory effect of aflibercept on the phagocytosis of freshly prepared pig RPE cells was also seen by the same group [13].…”

Section: Discussionsupporting

confidence: 53%

Ranibizumab and Bevacizumab but Not Aflibercept Inhibit Proliferation of Primary Human Retinal Pigment Epithelium in vitro

et al. 2018

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Aim: Treatment of exudative age-related macular degeneration by using vascular endothelial growth factor (VEGF) antagonists is the gold standard today. So far, several bioactive molecules have been approved for therapeutic use. In this study, we investigate the effects of ranibizumab (Lucentis®), bevacizumab (Avastin®), and aflibercept (Eylea®) on primary human retinal pigment epithelial (hRPE) cells in vitro. Methods: hRPE cells were prepared from donor eyes and cultured under standard culture conditions. Scleral fibroblasts also prepared from donor tissue served as physiological controls. The impact of the anti-VEGF molecules on cell viability was investigated with the trypan blue exclusion assay, whereas proliferation was measured using the MTT assay. Biological activity of the molecules was quantified in a VEGF-enzyme-linked immunosorbent assay (ELISA). Results: All tested substances were biologically active in vitro. They displayed no cytotoxicity on RPE cells or scleral fibroblasts. However, proliferation of RPE cells was significantly decreased after treatment with ranibizumab or bevacizumab but not with aflibercept. Conclusions: The humanized antibodies (fragments) interfered specifically with the RPE cells. The thereby measured inhibition of cell proliferation may indicate possible side effects on the physiology of RPE cells.

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Section: Discussionsupporting

confidence: 53%

Ranibizumab and Bevacizumab but Not Aflibercept Inhibit Proliferation of Primary Human Retinal Pigment Epithelium in vitro

et al. 2018

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“…41 Several studies have investigated whether the uptake of ranibizumab and bevacizumab impairs RPE cell proliferative, healing, and phagocytotic abilities. 42,43 In these studies, neither ranibizumab nor bevacizumab induced significant cell death following 7 days of treatment and no inhibition of VEGF secretion was observed after 3 days of culture. However, bevacizumab, but not ranibizumab, internalized into porcine RPE cells in vitro and accumulated in the cells.…”

mentioning

confidence: 99%

“…42 In a following study, bevacizumab, and to a lesser extent ranibizumab, were found to impair the proliferation of porcine RPE cells and to have no effect on wound healing. 43 Bevacizumab, but not ranibizumab, was found to reduce the phagocytotic function of RPE cells, indicating possible long-term effects of repeated bevacizumab treatment. 43 The selective uptake of bevacizumab, but not ranibizumab, may be owed to the presence of an Fc domain and sugar moieties on bevacizumab.…”

mentioning

confidence: 99%

“…43 Bevacizumab, but not ranibizumab, was found to reduce the phagocytotic function of RPE cells, indicating possible long-term effects of repeated bevacizumab treatment. 43 The selective uptake of bevacizumab, but not ranibizumab, may be owed to the presence of an Fc domain and sugar moieties on bevacizumab. The uptake of bevacizumab may be mediated by Fc-receptor mediated phagocytosis or via RPE cell mannose receptors and galectins.…”

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confidence: 99%

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Preclinical aspects of anti-VEGF agents for the treatment of wet AMD: ranibizumab and bevacizumab

Meyer

Holz

2011

Eye

116

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Three anti-vascular endothelial growth factor (VEGF) therapies are currently used for the treatment of patients with wet age-related macular degeneration (AMD): pegaptanib, ranibizumab, and bevacizumab. Ranibizumab is an antibody fragment approved for the treatment of wet AMD. Bevacizumab is a fulllength antibody registered for use in oncology but unlicensed for wet AMD. However, it is used off-label worldwide not only for wet AMD but also for various other ocular diseases associated with macular edema and abnormal vessel growth. We consider aspects of ranibizumab and bevacizumab in relation to their molecular characteristics, in vitro and in vivo properties, and preclinical safety data. Before 2009, most studies described the shortterm toxicity of bevacizumab in multiple cell types of the eye. Since 2009, an increasing number of studies have compared the properties of ranibizumab and bevacizumab and investigated their impact on retinal cell functioning. Compared with bevacizumab, ranibizumab neutralizes VEGF better at low concentrations, maintains efficacy for longer, and has a higher retinal penetration and potency. Studies in animals demonstrate ranibizumab to be better localized to the injected eye, whereas bevacizumab appears to have a greater effect in the fellow eye. In humans, a localized and systemic effect has been reported for both molecules. In conclusion, overlapping yet distinct pharmacological properties of ranibizumab and bevacizumab indicate that safety or efficacy data from one cannot be extrapolated to the other.

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“…This drug taken up into the cells assumingly affects the physiology of the cells like reduced phagocytic capacity and interference with protein synthesis [19,20].…”

Section: Introductionmentioning

confidence: 99%

Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept

Ranjbar

Brinkmann

Zapf

et al. 2016

Cell Physiol Biochem

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Background/Aims: VEGF-A is induced by oxidative stress, and functions as a survival factor for various cell types, including retinal pigment epithelial (RPE) cells. Anti-vascular endothelial growth factor (VEGF) drugs like aflibercept and bevacizumab have shown to be most effective in treating neovascular age-related macular degeneration (AMD), however uptake of the drugs might lead to interference with cell physiology. Herein, we evaluated the significance of the Fc receptor (FcR) within this context and moreover explored the impact of VEGF inhibition under normal conditions as well as under oxidative stress, in terms of potential adverse effects. Methods: ARPE-19 (human RPE) cells were treated with aflibercept and bevacizumab in presence or absence of H₂O₂ as oxidative stress stimulus. After 24h cells were evaluated for drug uptake, VEGF-A expression and secretion, levels of intracellular reactive oxygen species (ROS) as well as cell proliferation. Experiments were repeated with cells being pre-incubated with an FcR inhibitor prior to drug application. Results: Both drugs inhibited extracellular levels of VEGF-A and were taken up into the RPE, resulting in significantly reduced intracellular levels of VEGF-A. When oxidative stress was applied, intracellular ROS levels in cells treated with both drugs rose, and cell proliferation was reduced. Prior incubation with the FcR inhibitor lessened the uptake of bevacizumab, but not aflibercept into RPE cells, and simultaneously enhanced cell survival under oxidative stress conditions. Conclusions: Our results indicate that uptake and accumulation of aflibercept and bevacizumab within RPE cells affect the intracellular VEGF-A metabolism negatively, leading to a biologically relevant reduced cell survival under oxidative stress. The FcR plays a substantial role in the uptake of bevacizumab, but not aflibercept, which allows an enhanced RPE cell survival through FcR blockage in an environment dominated by oxidative stress, as clinically significant for various inflammatory retinal disorders.

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Intracellular bevacizumab reduces phagocytotic uptake in RPE cells

Abstract: The uptake of bevacizumab reduces phagocytosis in RPE cells, which indicates possible long-term effects of repeated bevacizumab treatment.

Cited by 46 publications

References 25 publications

Ranibizumab and Bevacizumab but Not Aflibercept Inhibit Proliferation of Primary Human Retinal Pigment Epithelium in vitro

Ranibizumab and Bevacizumab but Not Aflibercept Inhibit Proliferation of Primary Human Retinal Pigment Epithelium in vitro

Preclinical aspects of anti-VEGF agents for the treatment of wet AMD: ranibizumab and bevacizumab

Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept

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