GB10, a best-in-class antibody fusion protein targeting VEGF/Ang-2, exhibits promising therapeutic efficacy for neovascular eye diseases

Abstract Background In clinical practice, anti-vascular endothelial growth factor (VEGF) therapies have been successfully applied to patients with neovascular eye diseases. However, unmet clinical needs have not yet been fully addressed, as about 20% of patients do not response to anti-VEGF monotherapies, meanwhile, the high frequency of intravitreal (IVT) injections imposes a significant burden on patients. To overcome these challenges, we developed a novel antibody fusion protein GB10 consisting of a VEGF-Trap and an anti-angiopoietin 2 (Ang-2) variable heavy domain of heavy-chain antibody (VHH) to inhibit the pro-angiogenic pathways of VEGF and Ang-2 simultaneously for enhanced and more enduring efficacy. The activity and developability of GB10 were characterized. Methods We first explored two categorical formats for molecular construction and selected the format that demonstrated the best activity and CMC-related properties for the generation of GB10. Subsequently, we evaluated the multi-targeting capability of GB10 using bridging enzyme-linked immunosorbent assay (ELISA) and bio-layer interferometry (BLI), followed by a side-by-side comparison of the in vitro activities of GB10 and faricimab, the only marketed bispecific antibody for neovascular eye diseases, through assays such as VEGF reporter assay, human umbilical vein endothelial cells (HUVEC) proliferation, Ang-2 blocking ELISA, and Tie-2 phosphorylation. The in vivo efficacy of GB10 and faricimab was next evaluated using a non-human primate model of laser-induced choroidal neovascularization (CNV). Finally the developability of GB10 was evaluated by intraocular pharmacokinetics and stress test. Results GB10 bound VEGF and Ang-2 simultaneously with high affinity, and exhibited superior activity in vitro in inhibiting the VEGF and Ang-2 signaling pathways compared to faricimab. In vivo, GB10 demonstrated greater efficacy and durability compared to faricimab in a CNV model. GB10 also possessed a longer half-life in vitreous measured in a rabbit model. Moreover, GB10 showed excellent injectability and stability at a high-concentration of 140 mg/mL. Conclusions The superb efficacy and favorable developability profile make GB10 a potential best-in-class therapy for patients with neovascular eye diseases, warranting further evaluation in clinical settings.