Compstatins: the dawn of clinical C3-targeted complement inhibition

The compstatin family of complement C3 inhibitors was identified in 1996 by phage display screening and subsequently optimized toward subnanomolar affinity. Compstatin analogs feature a narrow species specificity, excellent plasma stability, and favorable pharmacokinetic profiles. Early proof-of-concept studies showed potent systemic anti-inflammatory and organ-protective effects of compstatins in nonhuman primate models of polytrauma-induced hemorrhagic shock, hemodialysis-induced inflammation, xenotransplantation, and human leukocyte antigen–incompatible kidney transplantation, among others. A PEGylated, second-generation compstatin derivative (pegcetacoplan, Empaveli/Aspaveli; Apellis Pharmaceuticals) was approved in 2021 for the treatment of paroxysmal nocturnal hemoglobinuria and is evaluated in further indications. This approval not only serves as validation of the compstatin technology in a clinical setting but also opens up new opportunities for therapeutic C3 modulation. Next-generation derivatives with improved target affinities and pharmacokinetic properties (e.g., AMY-101; Amyndas Pharmaceuticals) are tested in clinical trials for periodontal disease, COVID-19, and other diseases. The enhanced intraocular residence and retinal distribution of the latest-generation compstatins may point to more tailored therapeutic solutions for retinal pathologies driven by C3 dysregulation such as age-related macular degeneration. Growing evidence over the past 15 years has indicated that C3 inhibition may hold therapeutic promise in chronic neurodegeneration. Despite the growing recognition of the complement system as a major contributor to a variety of clinical conditions, the therapeutic arsenal has remained scarce. The introduction of an anti-C5 antibody in 2007 raised confidence in complement-targeted therapy. However, it became apparent that inhibition of late-stage effector generation might not be sufficient in multifactorial complement disorders. Upstream intervention at the level of C3 activation has therefore been considered promising. The approval of pegcetacoplan, a C3 inhibitor of the compstatin family, in 2021 served as critical validation of C3-targeted treatment. This review delineates the evolution of the compstatin family from its academic origins to the clinic and highlights current and potential future applications of this promising drug class in complement diseases. Despite the growing recognition of the complement system as a major contributor to a variety of clinical conditions, the therapeutic arsenal has remained scarce. The introduction of an anti-C5 antibody in 2007 raised confidence in complement-targeted therapy. However, it became apparent that inhibition of late-stage effector generation might not be sufficient in multifactorial complement disorders. Upstream intervention at the level of C3 activation has therefore been considered promising. The approval of pegcetacoplan, a C3 inhibitor of the compstatin family, in 2021 served as critical validation of C3-targeted treatment. This review delineates the evolution of the compstatin family from its academic origins to the clinic and highlights current and potential future applications of this promising drug class in complement diseases. prevalent ocular inflammatory disease that leads to blurring or loss of vision in the center of the visual field and can be divided in ‘wet’ and ‘dry’ subtypes. method to systematically investigate structure–activity relationships. Several peptides are generated where each amino acid position is changed to alanine one-by-one and compared with the original peptide sequence. progressive neurodegenerative disease with motor neuron loss leading to loss of muscle control. small effector protein generated during complement activation that can exert chemotactic, inflammatory, anaphylactic, and/or other biological activities. a rare renal disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. It is strongly linked to complement dysregulation mainly fueled by genetic or acquired defects of the complement alternative pathway. disorders driven by an impaired regulation of complement. central protease complexes that are able to cleave C3 and C5 respectively. The convertase complexes are composed of several activated complement proteins (i.e., C2b, C3b, C4b, Bb). chronic autoimmune neuromuscular disease with autoantibodies against nicotinic acetylcholine receptors. It leads to skeletal muscle weakness due to reduced signal transduction at the junction between nerve and muscle. advanced stage of nonexudative age-related macular degeneration (dry AMD) leading to the irreversible loss of central vision. It is characterized by lesions formed by the deterioration of the photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris (network of small vessels supporting the retina). tightly regulated protein networks that protect the body from microbial intruders and other threats that subvert its homeostasis through danger sensing, proinflammatory signaling, and generation of effector molecules that contribute to leukocyte activation, migration into tissues, and pathogen clearance. an oligomeric protein of the C-type lectin family that serves as a pattern recognition receptor binding to carbohydrate signatures found on pathogenic micro-organisms and apoptotic cells. terminal multiprotein complex of the complement cascade, composed of the complement components C5b, C6, C7, C8, and multiple copies of C9. It can insert into the cell membrane, forming a pore. stability of a therapeutic compound against degradation, oxidation, and conjugation by metabolic pathways, such as proteases and liver cytochromes. an umbrella term comprising rare and heterogeneous syndromes characterized by acute inflammation of the optic nerve (optic neuritis) and the spinal cord (myelitis). In the majority of cases, this is caused by autoantibodies against aquaporin 4. method to systematically investigate structure–activity relationships. Several peptides are generated where each amino acid position is changed one-by-one to the N-methylated version of the amino acid and compared with the original peptide sequence. It is used as a general strategy to reduce binding-related entropy loss of peptides by providing local constraints to the peptide backbone. binding of an opsonin (e.g., antibody or complement protein C3b, C4b) to an epitope of a pathogen or onto cells to serve as a danger signal and/or to trigger phagocytosis. a rare acquired hematological disorder in which complement dysregulation on the surface of erythrocytes lacking the glycophosphatidylinositol-anchored complement regulatory proteins CD55 and CD59 leads to chronic intravascular hemolysis, complement-mediated anemia, and transfusion dependency. peptide derivative that consists of an inverted amino acid sequence and D-stereochemistry compared with the original peptide. transplant of organs or tissues from one to another species.