Treatment of ocular disease is hindered by the presence of the blood-retinal barrier, which restricts access of systemic drugs to the eye. Intravitreal injections bypass this barrier, delivering high concentrations of drug to the targeted tissue. However, the recommended dosing interval for approved biologics is typically 6–12 weeks, and frequent travel to the physician’s office poses a substantial burden for elderly patients with poor vision. Real-world data suggest that many patients are under-treated. Here, we investigate IgMs as a novel platform for treating ocular disease. We show that IgMs are well-suited to ocular administration due to moderate viscosity, long ocular exposure, and rapid systemic clearance. The complement-dependent cytotoxicity of IgMs can be readily removed with a P436G mutation, reducing safety liabilities. Furthermore, dodecavalent binding of IgM hexamers can potently activate pathways implicated in the treatment of progressive blindness, including the Tie2 receptor tyrosine kinase signaling pathway for the treatment of diabetic macular edema, or the death receptor 4 tumor necrosis family receptor pathway for the treatment of wet age-related macular degeneration. Collectively, these data demonstrate the promise of IgMs as therapeutic agonists for treating progressive blindness.

血视网膜屏障的存在阻碍了眼部疾病的治疗，该屏障限制了全身药物进入眼睛。玻璃体内注射绕过这个屏障，将高浓度的药物输送到目标组织。然而，已批准生物制剂的推荐给药间隔通常为 6-12 周，而频繁前往医生办公室给视力不佳的老年患者带来了沉重负担。现实世界的数据表明，许多患者没有得到充分的治疗。在这里，我们研究 IgM 作为治疗眼部疾病的新平台。我们发现，由于 IgM 粘度适中、眼部暴露时间长且全身清除速度快，因此 IgM 非常适合眼部给药。IgM 的补体依赖性细胞毒性可以通过 P436G 突变轻松消除，从而减少安全隐患。此外，IgM 六聚体的十二价结合可以有效激活与治疗进行性失明有关的通路，包括用于治疗糖尿病性黄斑水肿的 Tie2 受体酪氨酸激酶信号通路，或用于治疗湿性失明的死亡受体 4 肿瘤坏死家族受体通路。年龄相关性黄斑变性。总的来说，这些数据证明了 IgM 作为治疗进行性失明的治疗激动剂的前景。