Intravitreal (IVT) injection of anti-vascular endothelial growth factor (anti-VEGF) has greatly improved the treatment of many retinal disorders, including wet age-related macular degeneration (wAMD), which is the third leading cause of blindness. However, frequent injections can be difficult for patients and may lead to various risks such as elevated intraocular pressure, infection, and retinal detachment. To address this issue, researchers have found that IVT injection of anti-VEGF proteins at their maximally viable concentration and dose can be an effective strategy. However, the intrinsic protein structure can limit the maximum concentration due to stability and solution viscosity. To overcome this challenge, we developed a novel anti-VEGF protein called nanoFc by fusing anti-VEGF nanobodies with a crystallizable fragment (Fc). NanoFc has demonstrated high binding affinity to VEGF₁₆₅ through multivalency and potent bioactivity in various bioassays. Furthermore, nanoFc maintains satisfactory chemical and physical stability at 4°C over 1 month and is easily injectable at concentrations up to 200 mg/mL due to its unique architecture that yields a smaller shape factor. The design of nanoFc offers a bioengineering strategy to ensure both strong anti-VEGF binding affinity and high protein concentration, with the goal of reducing the frequency of IV injections.

中文翻译：

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一种高亲和力、高浓度的生物工程抗 VEGF 蛋白，用于玻璃体内治疗湿性年龄相关性黄斑变性


玻璃体内（IVT）注射抗血管内皮生长因子（抗VEGF）极大地改善了许多视网膜疾病的治疗，包括湿性年龄相关性黄斑变性（wAMD），这是导致失明的第三大原因。然而，频繁注射会给患者带来困难，并可能导致眼压升高、感染、视网膜脱离等多种风险。为了解决这个问题，研究人员发现，IVT 注射最大可行浓度和剂量的抗 VEGF 蛋白可能是一种有效的策略。然而，由于稳定​​性和溶液粘度，内在的蛋白质结构会限制最大浓度。为了克服这一挑战，我们通过将抗 VEGF 纳米抗体与可结晶片段 (Fc) 融合，开发了一种名为 nanoFc 的新型抗 VEGF 蛋白。 NanoFc 在各种生物测定中通过多价和有效的生物活性证明了与 VEGF ₁₆₅的高结合亲和力。此外，nanoFc 在 4°C 下可在 1 个月内保持令人满意的化学和物理稳定性，并且由于其独特的结构可产生更小的形状因子，因此可以在高达 200 mg/mL 的浓度下轻松注射。 nanoFc的设计提供了一种生物工程策略，以确保强的抗VEGF结合亲和力和高蛋白浓度，以减少静脉注射的频率。