Abstract

DO.01.04

Intracellular and extracellular effects of the VEGF antagonists Avastin and Lucentis

Alexa Klettner
Klinik für Ophthalmologie, Campus Kiel, Universitätsklinikum Schleswig-Holstein, Kiel

The usage of VEGF-antagonists is an effective treatment for the exudative form of the age-related macular degeneration. Pegaptanib (Macugen®), Ranibizumab (Lucentis®) and Bevacizumab (Avastin®) are currently in clinical use. Ranibizumab and Bevacizumab are developed from the same murine monoclonal antibody and often considered interchangeable. Ranibizumab and Bevacizumab bind to all isoforms of VEGF, in contrast to Pegaptanib, which only binds to VEGF 165. The binding occurs extracellularly and prohibits the VEGFR-2 mediated signal transduction cascade induction, inhibiting the angiogenic as well as other effects of VEGF binding. Bevacizumab and Ranibizumab bind to the receptor-binding-domain, while Pegaptanib bind to the heparin-binding domain and is unlikely to prohibit the binding to VEGFR-2. In our studies, we could show that the inhibition of VEGF exceeded the presence of the inhibitor in our system. Both Ranibizumab and Bevacizumab exhibited an effect on intracellular VEGF, maybe by interfering with positive feedback mechanisms, as described for endothelial cells (Deudero et al., 2008). At least in our system, however, the inhibition of VEGFR-2 did not result in a decreased VEGF secretion. In contrast, we detected an uptake and storage of Bevacizumab but not of Ranibizumab in RPE cells for at least 7 days. As the duration of VEGF inhibition does not differ between Bevacizumab and Ranibizumab, the uptake is unlikely to contribute to the VEGF inhibition. However, this shows that Bevacizumab and Ranibizumab are not identical in their effects on RPE cells. The effects of VEGF-inhibitors on RPE cells exceed a dose-dependent neutralization of VEGF and need to be examined further.

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