Emerging opportunities for C3 inhibition in the eye

Elsevier

Available online 2 July 2022, 101633

Seminars in ImmunologyAbstract

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.

AbbreviationsAMD

age-related macular degeneration

A2E

N-retinylidene-N-retinylethanolamine

CNV

choroidal neovascularization

DME

diabetic macular edema

EFEMP-1

EGF-containing fibulin-like extracellular matrix protein-1

EMA

European medicines agency

FDA

food and drug administration

IAP

integrin associated protein

iRORA

incomplete RPE and outer retina atrophy

MAC

membrane attack complex

MNV

macular neovascularization

mTOR

mammalian target of rapamycin

PDR

proliferative diabetic retinopathy

POAG

primary open angle glaucoma

RPE

retinal pigment epithelium

RVO

retinal vein occlusion

SNP

single nucleotide polymorphism

TSP-1

thrombospondin – 1

VEGF

vascular endothelial growth factor

Keywords

Age-related macular degeneration

Geographic atrophy

Complement

C3

Retina

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© 2022 Published by Elsevier Ltd.

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