Emerging opportunities for C3 inhibition in the eye

• Published in: Seminars in immunology 2022-01, Vol.59, p.101633-101633, Article 101633
• Main Authors: Kim, Benjamin J., Liu, Tianyu, Mastellos, Dimitrios C., Lambris, John D.
• Format: Article
• Language: English
• Subjects: Age-related macular degeneration; Complement; Complement Activation; Geographic atrophy; Geographic Atrophy - drug therapy; Geographic Atrophy - etiology; Humans; Macular Degeneration - complications; Macular Degeneration - drug therapy; Retina
• ISSN: 1044-5323; 1096-3618
• DOI: 10.1016/j.smim.2022.101633

The eye presents a unique opportunity for complement component 3 (C3) therapeutics. Drugs can be delivered directly to specific parts of the eye, and growing evidence has established a pivotal role for C3 in age-related macular degeneration (AMD). Emerging data show that C3 may be important to the pathophysiology of other eye diseases as well. This article will discuss the location of C3 expression in the eye as well as the preclinical and clinical data regarding C3’s functions in AMD. We will provide a comprehensive review of developing C3 inhibitors for the eye, including the Phase 2 and 3 data for the C3 inhibitor pegcetacoplan as a treatment for the geographic atrophy of AMD. Developing evidence also points toward C3 as a therapeutic target for stages of AMD preceding geographic atrophy. We will also discuss data illuminating C3’s relationship to other eye diseases, such as Stargardt disease, diabetic retinopathy, and glaucoma. In addition to being a converging point and centerpiece of the complement cascade, C3 has broad effects as a multifaceted controller of opsonophagocytosis, microglia/macrophage recruitment, and downstream terminal pathway activity. C3 is a crucial player in the pathophysiology of AMD but also seems to have importance in other diseases that are major causes of blindness. Directions for further investigation will be highlighted, as culminating evidence suggests that we may be approaching an era of C3 therapeutics for the eye.