Affinity and Potency of RTH258 (ESBA1008), a Novel Inhibitor of Vascular Endothelial Growth Factor A for the Treatment of Retinal Disorders

Abstract

Purpose: RTH258 is a humanized monoclonal single-chain Fv (scFv) antibody fragment targeting VEGF-A. In this study, we characterized affinity and in vitro potency of RTH258 in comparison to the VEGF inhibitors bevacizumab, ranibizumab, and aflibercept under standardized conditions.

Methods: The properties of RTH258 and the other VEGF inhibitors were determined and compared under standardized conditions. Binding kinetics to human VEGF-A were evaluated using standardized surface plasmon resonance technology (SPR). Blockade of VEGF binding to its receptor VEGFR-2 was assessed in a highly sensitive competition ELISA. Potency was determined in primary human endothelial cells expressing VEGFR-2.

Results: When compared under standardized conditions, RTH258 exhibited similar high affinity to human VEGF as ranibizumab and superior affinity compared to bevacizumab. RTH258 inhibited binding of VEGF to its receptor and, similarly to other VEGF antagonists, RTH258 potently inhibited VEGF-induced proliferation of primary human endothelial cells.

Conclusions: RTH258 possesses valuable pharmacological properties, namely high affinity to VEGF and a high VEGF neutralizing capacity comparable to the anti-VEGF compounds that are in clinical use for the treatment of retinal disorders. Combined with excellent biophysical properties such as high solubility and stability, up to 6 mg can be administered, which represents a molar excess higher than 10- and 20-fold over aflibercept and ranibizumab clinical doses, respectively. Therefore, RTH258 may confer advantages over currently available therapies, potentially allowing for less frequent dosing resulting in a reduced treatment burden. Further clinical development of RTH258 is ongoing.