Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture

Deepika Malik, Mohamed Tarek, Javier Caceres del Carpio, Claudio Ramirez, David Boyer, M Cristina Kenney, Baruch D Kuppermann, Deepika Malik, Mohamed Tarek, Javier Caceres del Carpio, Claudio Ramirez, David Boyer, M Cristina Kenney, Baruch D Kuppermann

Abstract

Purpose: To compare the safety profiles of antivascular endothelial growth factor (VEGF) drugs ranibizumab, bevacizumab, aflibercept and ziv-aflibercept on retinal pigment epithelium cells in culture.

Methods: Human retinal pigment epithelium cells (ARPE-19) were exposed for 24 h to four anti-VEGF drugs at 1/2×, 1×, 2× and 10× clinical concentrations. Cell viability and mitochondrial membrane potential assay were performed to evaluate early apoptotic changes and rate of overall cell death.

Results: Cell viability decreased at 10× concentrations in bevacizumab (82.38%, p=0.0001), aflibercept (82.68%, p=0.0002) and ziv-aflibercept (77.25%, p<0.0001), but not at lower concentrations. However, no changes were seen in cell viability in ranibizumab-treated cells at all concentrations including 10×. Mitochondrial membrane potential was slightly decreased in 10× ranibizumab-treated cells (89.61%, p=0.0006) and 2× and 10× aflibercept-treated cells (88.76%, 81.46%; p<0.01, respectively). A larger reduction in mitochondrial membrane potential was seen at 1×, 2× and 10× concentrations of bevacizumab (86.53%, 74.38%, 66.67%; p<0.01) and ziv-aflibercept (73.50%, 64.83% and 49.65% p<0.01) suggestive of early apoptosis at lower doses, including the clinical doses.

Conclusions: At clinical doses, neither ranibizumab nor aflibercept produced evidence of mitochondrial toxicity or cell death. However, bevacizumab and ziv-aflibercept showed mild mitochondrial toxicity at clinically relevant doses.

Keywords: Angiogenesis; Macula; Treatment Medical.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1
Figure 1
Cell viability assay. (A) No significant decrease in % cell viability was seen in 1/2×, 1×, 2×, 10× ranibizumab-treated ARPE-19 cells, p>0.05. (B) Cell viability decreased to 82% in 10× bevacizumab-treated cells when compared with controls (p=0.0002). No statistically significant change in cell viability was observed on treatment with either 1/2×, 1×, or 2× concentration of bevacizumab. (C) A statistically significant decrease in cell viability (83%) was seen in 10× aflibercept-treated cells (p=0.0001). There was no significant change in 1/2×, 1× and 2× concentrations when compared with controls, p>0.05. (D) Ziv-aflibercept-treated ARPE-19 cells showed a 77% reduction of cell viability at 10 concentration, p

Figure 2

Mitochondrial membrane potential (ΔΨm) assay:…

Figure 2

Mitochondrial membrane potential (ΔΨm) assay: (A) There was a statistically significant decrease in…

Figure 2
Mitochondrial membrane potential (ΔΨm) assay: (A) There was a statistically significant decrease in mitochondrial membrane potential that was observed at 10× concentration of ranibizumab, p
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Figure 2
Figure 2
Mitochondrial membrane potential (ΔΨm) assay: (A) There was a statistically significant decrease in mitochondrial membrane potential that was observed at 10× concentration of ranibizumab, p

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