January/February 2022
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The complement cascade has been implicated in the development of age-related macular degeneration (AMD), and may serve as an effective therapeutic target in patients with geographic atrophy (GA). Many retina specialists have not thought deeply about the complement pathway since their formal medical school education—and for good reason, given the specialized nature of their field, high patient and surgical volumes, and the irrelevance of the complement cascade in day-to-day practice.
However, therapies in the AMD pipeline targeting the complement system have renewed the need for retina specialists to understand how this element of the innate immune system affects the genesis and progression of AMD.
The complement system’s elegance is also its complexity, and diving into the overall system without a foundational understanding of the scheme may lead to information overload. With that in mind, it may be wise to remember the four major tenets of the complement system: activation of the complement system, C3 convertase function, C5 convertase function, and formation of membrane attack complex. Building an education of the complement system from those four points will facilitate reorientation with this biologic pathway.
Steps of the complement pathway
The complement pathway begins with the classical, lectin, and alternative activation pathways.1
These converge on C3 cleavage by C3 convertases.1
This process then leads to C5 cleavage by C5 convertases.1
And, finally, assembly of the membrane attack complex.1
There have been multiple shots on goal when it comes to developing a therapy for GA, and dozens of companies are racing toward finding a target in the complement cascade that could yield a safe and effective treatment. Although numerous clinical trials in GA have yet to yield a therapy that has been approved by the US FDA, savvy retina specialists have noted that data from these studies have helped focus and refine investigations that came after them.
This is not a winner-take-all competition akin to the Space Race of the middle 20th century, but rather a community effort to build a robust set of treatment options for patients who have heretofore been unable to receive therapy. To that end, we invite readers to use any of the illustrated assets in this piece for their own educational purposes. Borrow them for your podium presentations, for your weekly rounds, for teaching trainees—and do so in the spirit of specialty-wide collaboration so that we may further education in the field.
Charles C. Wykoff, MD, PhD
• Director of Research, Retina Consultants of Texas/Retina Consultants of America, Houston
• Deputy Chair for Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston
ccwmd@retinaconsultantstexas.comFinancial disclosure: Research Grants and Scientific Advisor (Apellis, Gyroscope, Iveric Bio, NGM)
Opsonization of pathogens for subsequent engulfment by phagocytes1
Enhancement of antibody-dependent and -independent immune pathways1
Generation of the membrane attack complex (MAC), which lyses pathogens via generation of cell membrane pores1
Click the numbered beacons on the pathways to watch videos, which describe the steps in greater detail.
1
2
3
4
5
6
What is the role of the complement system in retinal immunity?
Contributes to innate immune defense and regulates ocular immune privilege2
Serves as a target for therapeutic intervention in inflammatory retinal diseases2
Protects the retina from exogenous and endogenous insults by complementing antibodies and phagocytes to clear pathogens from host tissue2
Contributes to retinal diseases when dysregulated by promoting pathological ocular inflammation and cell death2
Why is the complement system a rational target for treating retinal disease?
Complement system activity, including expression of complement components C1r, C1q, C2, C3, C4, fB, and fH, has been identified in the retina/retinal pigment epithelium and choroid.2
Complement system components undergo age-dependent upregulation and activation, as observed in animal models.2
Complement activation has been observed in diverse retinal disorders with inflammatory involvement, including: Age-related macular degeneration, including dry AMD (geographic atrophy); glaucoma; uveitis; diabetic retinopathy.2
A variety of pathogenic molecules implicated in diverse diseases, including: C-reactive protein (CRP); phosphatidylserine; amyloid; and cellular debris, are all under investigation as potential activators of the complement pathway.
COMPLEMENT COMPONENTS IN THE RETINA
COMPLEMENT TARGETS BEING PURSUED AS OF JANUARY 2022:
COMPLEMENT TARGETS BEING PURSUED AS OF JANUARY 2022:
There are numerous retinal disease therapies in development targeting various aspects of the complement system. Here we would like to acknowledge a few whose advertising support made this interactive overview possible. See Retina Today’s 2021 Retina Pipeline: A View Into Ongoing Innovation [Interactive] for a full list of therapies in clinical development for AMD treatment.
Click each logo for more information on each company and their therapy.
Candidate: Pegcetacoplan
Target: C3 Inhibition
Apellis in the News [EyeWire+] → Visit Company Website →
Candidate: ALXN2040 (danicopan)
Target: Complement Factor D Therapy
Alexion in the News [EyeWire+] →
Candidate: ANX007
Target: C1q Inhibition
Candidate: GEM103
Target: Complement Factor H Therapy
References:
1. Haines JL, Hauser MA, Schmidt S, Scott WK, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419-421.
2. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-389.
3. Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421-424.
4. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005;102:7227-7232
Retina Today encourages you to use these materials in presentations or whatever purposes you think are appropriate. We're in this together because a better understanding of the complement cascade will help clinicians push this space forward.
Download video and image source files or a Powerpoint below.
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Retina Today, February 2022
Namrata Saroj, OD
• Principal, All Eyes Consulting, New York
• Namrata.saroj@gmail.com
• Financial disclosure: Consultant (Apellis, Annexon, Gemini)
References:
1. Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The complement system and innate immunity. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27100/.
2. Xu H, Chen M. Targeting the complement system for the management of retinal inflammatory and degenerative diseases. Eur J Pharmacol. 2016;787:94-104.
3. Walport MJ. Complement: First of two parts. N Engl J Med. 2001;344(14):1058-1066.
4. Kaiser P. Retina pipeline: a view into ongoing innovation. Retina Today. 2020;15(8).