Targets for Complement-Mediated Disease

Complement-mediated diseases encompass a group of disorders characterized by dysregulation or aberrant activation of the complement system—a crucial component of innate immunity. The targets listed here are integral proteins and regulators of the complement cascade, including classical, lectin, and alternative pathways, as well as terminal pathway components and key regulatory factors. Understanding these molecular targets provides deep mechanistic insight into how inappropriate complement activation or insufficient regulation leads to tissue damage, inflammation, and pathology in diseases such as atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), and others. Detailed molecular characterization of these targets enables identification of precise intervention points for therapeutic modulation, supports rational drug design (e.g., monoclonal antibodies, small molecule inhibitors, recombinant regulatory proteins), and informs biomarker development for diagnosis, prognosis, and treatment monitoring. Collectively, these targets reveal the critical nodes of complement activation, amplification, and regulation that drive disease progression, and offer a framework for the development and clinical translation of targeted complement therapeutics.

Classical Pathway Initiators And Components

This category includes complement components that initiate and propagate the classical pathway, one of the main routes of complement activation implicated in complement-mediated diseases. These targets are central to the recognition and early amplification of the complement cascade, leading to downstream effector functions. The main targets are Complement C1r (C1R), Complement C1s (C1S), Complement C2 (C2), and Complement C4B (C4B). Dysfunction or overactivation of these proteins can result in excessive complement activation, immune complex-mediated inflammation, and tissue injury.

Complement C1r (C1R)

Complement C1r (C1R) is a serine protease that forms part of the C1 complex (with C1q and C1s) initiating the classical complement pathway. Structurally, C1r contains CUB, EGF-like, CCP, and serine protease domains, and is activated by conformational changes upon C1q binding to immune complexes. Activated C1r cleaves and activates C1s, propagating the cascade. Mutations or dysregulation can lead to uncontrolled classical pathway activation, as seen in immune complex-mediated diseases. Therapeutically, C1r is a potential target for inhibitors that block classical pathway initiation (e.g., anti-C1s monoclonal antibodies in clinical trials).

Complement C1s (C1S)

Complement C1s (C1S) is another serine protease of the C1 complex, activated by C1r. It cleaves C4 and C2 to form the C3 convertase (C4b2a), a critical amplification step. C1s contains similar modular domains as C1r. Overactivation of C1s leads to excessive complement activation and tissue damage, implicated in diseases like lupus nephritis. C1s is a direct therapeutic target; anti-C1s antibodies (e.g., sutimlimab) are approved for treating cold agglutinin disease, validating its pathogenic role.

Complement C2 (C2)

Complement C2 (C2) is a serine protease cleaved by C1s to form the C3 convertase (C4b2a). C2 consists of a CUB domain, vWFA domain, and serine protease domain. Genetic deficiencies or gain-of-function mutations in C2 can predispose to infections or autoimmunity, respectively. C2 is a biomarker for classical pathway activity and a potential, though less direct, drug target.

Complement C4B (C4B)

Complement C4B (C4B) is one of two C4 isotypes (C4A, C4B) cleaved by C1s to form C4b, which binds C2a to assemble the classical pathway C3 convertase. C4B has a thioester domain enabling covalent attachment to target surfaces. Genetic deficiency or abnormal activation of C4B is linked to increased susceptibility to autoimmune diseases. C4B levels serve as biomarkers for classical pathway activation.

Central Complement Components And Amplification

This category comprises the core components of the complement cascade responsible for amplification and propagation of the response, most notably Complement C3 (C3) and Complement Factor D (CFD). These proteins are pivotal in both the alternative and classical pathways, and their dysregulation is a hallmark of complement-mediated diseases. Overactivation leads to excessive opsonization, inflammation, and tissue injury.

Complement C3 (C3)

Complement C3 (C3) is the central hub of the complement system, undergoing cleavage to C3a (anaphylatoxin) and C3b (opsonin) by C3 convertases. Structurally, C3 contains an anaphylatoxin domain, thioester-containing domain, and C345C domain. C3b covalently attaches to target surfaces, enabling opsonization and further convertase formation. Dysregulation (e.g., C3 nephritic factor, C3 gain-of-function mutations) leads to uncontrolled amplification, as in C3 glomerulopathy. Therapeutics targeting C3 (e.g., pegcetacoplan) are in clinical use for PNH, highlighting its central pathogenic role.

Complement Factor D (CFD)

Complement Factor D (CFD) is a serine protease that cleaves Factor B when complexed with C3b, forming the alternative pathway C3 convertase (C3bBb). CFD is unique in being present at low concentration and is a rate-limiting step for alternative pathway activation. Overactive CFD leads to excessive alternative pathway amplification, implicated in diseases such as aHUS and C3G. Inhibitors of CFD (e.g., danicopan) are under clinical development.

Terminal Pathway Components And Effectors

This category includes complement proteins involved in the terminal pathway, leading to membrane attack complex (MAC) formation and cell lysis, as well as pro-inflammatory signaling via anaphylatoxins. The main targets are Complement C5 (C5), Complement C5a Receptor 1 (C5AR1), Complement C7 (C7), and Complement C9 (C9). Overactivation of the terminal pathway causes direct cell and tissue damage, a hallmark of several complement-mediated diseases.

Complement C5 (C5)

Complement C5 (C5) is cleaved by C5 convertases into C5a (potent anaphylatoxin) and C5b (initiator of MAC assembly). C5 contains macroglobulin domains and a CUB domain. C5a triggers inflammation via C5AR1, while C5b interacts sequentially with C6–C9 to form the MAC. Pathogenic overactivation leads to hemolysis and tissue injury in PNH and aHUS. C5 is the target of approved therapeutics (eculizumab, ravulizumab), which block its cleavage and prevent both C5a and MAC formation.

Complement C5a Receptor 1 (C5AR1)

Complement C5a Receptor 1 (C5AR1) is a G-protein coupled receptor for C5a, mediating its pro-inflammatory effects, including chemotaxis, oxidative burst, and cytokine release. C5AR1 is expressed on neutrophils and other immune cells. Overstimulation contributes to tissue injury in complement-mediated diseases. C5AR1 antagonists (e.g., avacopan) are approved for ANCA-associated vasculitis and under investigation for other indications.

Complement C7 (C7)

Complement C7 (C7) binds C5b-6 to initiate MAC assembly, inserting into membranes to facilitate cell lysis. C7 contains MACPF (membrane attack complex/perforin) domains. Deficiency protects against MAC-mediated lysis but predisposes to Neisseria infection. Overactivation promotes tissue injury in complement-mediated diseases. C7 is a potential, though less directly targeted, therapeutic node.

Complement C9 (C9)

Complement C9 (C9) is the final component of MAC, polymerizing to form a pore in target membranes. C9 also contains a MACPF domain. Excessive MAC formation leads to cell lysis and tissue injury in diseases like PNH. C9 is a biomarker for terminal pathway activation.

Complement Regulation And Control

This category encompasses key regulators that control complement activation and protect host tissues from damage. Dysregulation or deficiency of these proteins leads to unchecked complement activity, a major pathogenic mechanism in complement-mediated diseases. The main targets are Complement Factor H (CFH), Complement Factor H Related 1 (CFHR1), Complement Factor H Related 2 (CFHR2), Complement Factor I (CFI), and Complement Factor Properdin (CFP).

Complement Factor H (CFH)

Complement Factor H (CFH) is the principal regulator of the alternative pathway, composed of 20 CCP (SCR) domains mediating binding to C3b, polyanions, and host cell surfaces. CFH accelerates decay of the C3 convertase and acts as a cofactor for CFI-mediated C3b cleavage. Mutations or autoantibodies against CFH cause uncontrolled complement activation, leading to aHUS and C3G. Recombinant CFH and gene therapies are under development; CFH is also a diagnostic and prognostic biomarker.

Complement Factor H Related 1 (CFHR1)

Complement Factor H Related 1 (CFHR1) is structurally similar to CFH, containing five CCP domains. It modulates complement by competing for C3b binding and may act as a positive or negative regulator. Deletion of CFHR1 is associated with CFH autoantibody formation and aHUS. Its role as a biomarker and therapeutic target is under investigation.

Complement Factor H Related 2 (CFHR2)

Complement Factor H Related 2 (CFHR2) contains four CCP domains and can form dimers, modulating complement activity by binding C3b and C5 convertases. Altered CFHR2 function is implicated in C3G pathogenesis. Its precise role is still being elucidated, but it is considered a disease-relevant regulator.

Complement Factor I (CFI)

Complement Factor I (CFI) is a serine protease that cleaves and inactivates C3b and C4b in the presence of cofactors (CFH, C4BP, MCP). CFI contains a heavy chain (with FIMAC, SRCR, and LDLRA domains) and a light chain (serine protease domain). CFI deficiency or dysfunction leads to uncontrolled complement activation and is causative in aHUS and C3G. Recombinant CFI is being explored as a therapy.

Complement Factor Properdin (CFP)

Complement Factor Properdin (CFP) is the only known positive regulator of the alternative pathway, stabilizing the C3bBb convertase. CFP is composed of thrombospondin type 1 repeats. Overactivity promotes excessive amplification, while deficiency reduces alternative pathway function. CFP is a potential therapeutic target for dampening alternative pathway activity.