Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

Abstract

The complement system was discovered at the end of the 19th century as a heat-labile plasma component that “complemented” the antibodies in killing microbes, hence the name “complement.” Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. Significance Statement The complement system is the host’s defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host’s enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.

The Role of Complement in Synaptic Pruning and Neurodegeneration

“…Complement-induced cleavage products C3a and C5a are known to contribute to inflammation and activation of immune cells expressing C3aR or C5aR1 (G-protein coupled anaphylatoxin receptors), which leads to the induction of chemotaxis and cell activation including cytokine production. 1 , 41 Multiple injuries and/or stimuli can activate the complement system in the CNS, and as a result, the inflammatory response driven by the complement system is present in a wide range of diseases 42 ( Figure 1 ). While some disorders at least initially involve peripherally derived complement components owing to a compromised blood-brain barrier such as stroke, traumatic brain injury (TBI), and MS, CNS produced complement appears to be the dominant chronic source of these components in many neurodegenerative diseases.…”

Interaction Between the Complement System and Infectious Agents – A Potential Mechanistic Link to Neurodegeneration and Dementia

“…Of note, COVID-19 patients reportedly suffer from diverse neurological complications ( Stracciari et al, 2021 ). Although there is no direct evidence thus far to indicate causality between SARS-CoV-2 infection and neuropathology ( Maury et al, 2021 ), future research will show whether there is a causal link between overactivation of complement in response to SARS-CoV-2 and neurological symptoms or long-term complications of COVID-19 ( Garred et al, 2021 ).…”

Expanding Horizons in Complement Analysis and Quality Control

“…The requirements for that testing have been further influenced by the clinical introduction of complement therapeutics. Although the number of approved drugs that target complement is currently small, there is every indication that this will change soon, as outlined in recent reviews ( 54 , 55 ). The advent of the complement therapeutics, combined with recognition of the role of complement in a growing number of disorders, has put new demands on the clinical complement laboratory.…”