Grundlegende In-vitro-Untersuchungen zur VEGF-Inhibition mit Aflibercept: Gemeinsamkeiten und Unterschiede zu anderen VEGF-bindenden therapeutischen Proteinen

Zusammenfassung

Bei verschiedenen retinalen Erkrankungen kann eine gegen den vaskulären Endothelzell-Wachstumsfaktor (VEGF) gerichtete Therapie deren Verlauf günstig beeinflussen. Neben dem Anti-VEGF-Antikörper Bevacizumab (Avastin) und dem F(ab)-Fragment Ranibizumab (Lucentis) ist mit Aflibercept (Eylea) ein weiteres VEGF-bindendes Protein für die Therapie verfügbar. Die unterschiedliche Struktur und breitere Bindungsspezifität von Aflibercept könnten Konsequenzen für die klinische Anwendung haben, worauf auch grundlegende In-vitro-Untersuchungen und Tierexperimente Hinweise liefern. Obwohl die dominante Rolle des VEGF in pathologischen Prozessen, die mit Neovaskularisierung verbunden sind, außer Frage steht, kann auch der auf retinale Endothelzellen mitogen wirkende Plazentawachstumsfaktor (PlGF) modulierend wirken. Aflibercept kann PlGF ebenfalls hemmen und so möglicherweise in bestimmten Fällen Vorteile bieten. Ob das weitere Bindungsspektrum von Aflibercept und unterschiedliche Bindungsstärken der verschiedenen VEGF-bindenden Proteine tatsächlich in der therapeutischen Praxis zu Unterschieden führen, ist noch unklar. In-vitro-Untersuchungen belegen, dass Aflibercept die durch VEGF hervorgerufene Stimulation retinaler Zellen und Störung ihrer Schrankenfunktion hochwirksam verhindern oder wieder aufheben kann. Dabei zeigte sich allerdings, dass auch Aflibercept von wichtigen retinalen Zelltypen aufgenommen wird und normale Funktionen – Migration von Endothelzellen oder Phagozytose von Pigmentepithelzellen – beeinträchtigen kann. Vermutlich wird die Aufnahme durch die Fc-Antikörperdomäne begünstigt und dementsprechend ähneln sich in dieser Hinsicht Aflibercept und Bevacizumab, während von Ranibizumab nur geringe Mengen internalisiert werden. Die Aufnahme und Speicherung durch okuläre Zellen, die auch in vivo nach intravitrealer Injektion in Affenaugen beobachtet wurde, könnte bisher noch nicht erkannte Nebenwirkungen bei Langzeitanwendung bestimmter VEGF-bindender Proteine zur Folge haben.

Abstract

Patients suffering from various retinal diseases benefit from therapies directed against the vascular endothelial growth factor (VEGF). Aflibercept (Eylea) is another VEGF-binding protein available for intravitreal injection, in addition to the antibody bevacizumab (Avastin) and the F(ab) fragment ranibizumab (Lucentis). Afliberceptʼs distinct structure and broader binding specificity may have clinically relevant consequences, which is supported by basic in vitro studies and observations in animal eyes. All pathological processes involving neovascularisation are driven by the dominant action of VEGF, but other factors including placenta growth factor (PlGF), a mitogenic protein for retinal endothelial cells, potentially modulate its effects. Aflibercept is an inhibitor of both VEGF and PlGF and therefore may have superior therapeutic effects in some cases. However, whether or not afliberceptʼs broader binding specificity or different affinities for the different VEGF-binding proteins to VEGF result in substantially diverse therapeutic efficiencies has not yet been clarified. In vitro studies confirm that aflibercept efficiently prevents or normalises VEGF-stimulation of retinal cells and disturbance of their barrier function. These experiments also show that aflibercept is taken up by important retinal cell types and affects their normal function, i.e., migration of endothelial cells and phagocytosis of pigment epithelial cells. In accordance with a role of the Fc domains of aflibercept and bevacizumab, substantial amounts of both proteins are internalised, whereas only a small portion of ranibizumab enters the cells. Internalisation and storage by ocular cells, also observed in vivo after intravitreal injection into eyes of monkeys, may result in not yet recognised side effects during long-term treatment of patients with certain VEGF-binding proteins.

Schlüsselwörter

VEGF-Inhibitoren - Retina - Pharmakologie - diabetische Retinopathie - AMD - Makulaödem

Key words

VEGF-inhibitor - retina - pharmacology - diabetic retinopathy - AMD - macular oedema

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