Complement‐targeted therapeutics: An emerging field enabled by academic drug discovery

Abstract

Within a short few years, the number of complement inhibitors that are either approved for therapeutic application or evaluated in late-stage clinical trials has expanded remarkably. The sudden emergence of this target area in the pipelines of many biotech start-ups and even large pharmaceutical companies appears even more surprising when considering that the involvement of the complement system in various clinical conditions had long been recognized. In many aspects, however, the com-

Complement regulation in the eye: implications for age-related macular degeneration

“…Logically then, C3 is an attractive target, as it represents a central hub in the complement cascade. The compstatin family of C3 inhibitors have been at the center of investigation into C3 targeting in AMD for over a decade ( 111 ). As mentioned earlier, POT-4, a compstatin derivative, was studied in AMD clinical trials and did not demonstrate significant benefit ( 107 , 108 ).…”

MAP‐2:CD55 chimeric construct effectively modulates complement activation

“…Since then, at least eight more complement inhibitors have been approved by FDA, including avacopan, a small molecule that targets the C5 receptor 1 (C5aR1) for the treatment of ANCA vasculitis 42 ; sutimlimab, a monoclonal anti-C1s antibody for the treatment of cold agglutinin disease 43 ; pegcetacoplan, a C3 inhibiting peptide for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) 44 ; ravulizumab, a monoclonal anti-C5 also for the treatment of PNH; and finally, four different C1 esterase inhibitors for the treatment of hereditary angioedema. 45 Hopefully, many other complement therapeutics currently undergoing clinical trials 27 will soon reach the market, outstanding the importance of the complement system as a target for treating a variety of complement-driven diseases. While many strategies are currently being explored in pre-clinical studies and clinical trials, the use of bifunctional inhibitors deserves special attention.…”

“…25,26 Thus, the complement system has become a target of great interest for developing new therapies. 27 While many strategies are currently being explored in pre-clinical studies and clinical trials, the use of bifunctional inhibitors deserves special attention. 28,29 Such inhibitors may, in principle, be effective against a wider range of pathologies by simultaneously targeting different components or pathways and display reduced side effects by the lower doses necessary and/or their ability to reduce the accumulation of upstream activated complement fragments by acting at multiple points in the cascade.…”

“…Dysregulation of complement activation is involved in the pathogenesis of several inflammatory and autoimmune diseases 25,26 . Thus, the complement system has become a target of great interest for developing new therapies 27 . While many strategies are currently being explored in pre‐clinical studies and clinical trials, the use of bifunctional inhibitors deserves special attention 28,29 .…”

Complement inhibition in medicine: Hematology and beyond; complement inhibition in hematology: PNH and beyond

“…Lamers et al . in «Complement‐Targeted Therapeutics: An Emerging Field Enabled by Academic Drug Discovery» 7 recall the difficulties that researchers in the field had to face to pioneer and then develop complement inhibitors. Concerns about the safety of complement‐targeted interventions, the large number and high plasma concentrations of target proteins, and the complexity of the complement system's engagement in biological processes are among other factors that kept complement off the drug‐discovery radar for decades.…”