Complement cascade inhibition in geographic atrophy: a review

Abstract

The pathophysiology of dry age-related macular degeneration (AMD) and specifically geographic atrophy (GA) has been linked to the complement cascade. This cascade is part of the innate immune system and is made up of the classical, alternative, and lectin pathways. The pathways comprise a system of plasma and membrane-associated serum proteins that are activated with identification of a nonself entity. A number of these proteins have been implicated in the development and progression of dry AMD. The three pathways converge at C3 and cascade down through C5, making both of these proteins viable targets for the treatment of dry AMD. In addition, there are a number of complement factors, CFB, CFD, CFH, and CFI, which are potential therapeutic targets as well. Several different complement-directed therapeutics are being studied for the treatment of dry AMD with the hope that one of these approaches will emerge as the first approved treatment for GA.

Fig. 1. The complement cascade.

The complement cascade is a highly conserved component of the innate immune system consisting of serum and membrane-bound proteins. This proteolytic cascade is activated through 3 pathways: the classical, alternative, and lectin. The activation pathways converge at C3 convertase, activation of which cleaves C3 into C3a and C3b subunits. As the cascade continues, C5 convertase cleaves C5, leading to inflammasome and MAC formation, ultimately resulting in apoptosis.

Fig. 2. Evidence of complement activity in the formation of drusen [30].

Figure used with permission: Copyright (2005) National Academy of Sciences, USA.

Fig. 3. Blocking C5a demonstrated a 60% reduction in retina loss in a mouse model.

Blocking C5 activation, which prevents the formation of both C5a and C5b, improved retinal protection over blocking C5a alone. [34]. C5a is required for photoreceptor loss. a Anti-C5a (a-C5a) inhibits C5a binding to C5aR on the surface of 293 cells transfected with C5aR (CD88). b Flow cytometry analysis of CD11b+CD45hi mononuclear phagocytes in the neural retina of mice treated with control or C5a neutralizing Abs 3 days following NaIO₃ administration, n = 6. c Effect of C5a and C5 blocking Abs or isotype control Abs (Ctrl) on retina degeneration as measured by SD-OCT 7 days after NaIO3 administration. d Representative H&E stained sections of the central retina 7 days after NaIO3 administration. e POS length and RPE integrity measured in horizontal sections along the temporal-nasal axis of the mouse retina. Error bars indicate ±SEM, n = 3–4 naive and Ctrl, n = 7 a-C5a and a-C5. Naive = not NaIO3 treated. Scale bar = 10 μm. Central is 500 μm from optic nerve and periphery is 500–1750 μm. Experiments were repeated at least twice with similar results. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by one-way ANOVA with Tukey’s multiple comparisons test. INL inner nuclear layer, ONL outer nuclear layer, POS photoreceptor outer segments, RPE retinal pigmented epithelia, Ch choroid. Figure used under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/; no changes were made).

Fig. 4. Mean change from baseline in square root GA lesion area over 12 months.

AACP 2 mg B ACP 4 mg.