Clinical promise of next-generation complement therapeutics

Abstract

The complement system plays a key role in pathogen immunosurveillance and tissue homeostasis. However, subversion of its tight regulatory control can fuel a vicious cycle of inflammatory damage that exacerbates pathology. The clinical merit of targeting the complement system has been established for rare clinical disorders such as paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. Evidence from preclinical studies and human genome-wide analyses, supported by new molecular and structural insights, has revealed new pathomechanisms and unmet clinical needs that have thrust a new generation of complement inhibitors into clinical development for a variety of indications. This review critically discusses recent clinical milestones in complement drug discovery, providing an updated translational perspective that may guide optimal target selection and disease-tailored complement intervention.

Fig. 1 |. Simplified scheme of the complement cascade with disease-relevant effector functions and major drug target classes.

Whereas complement typically exerts its various effector functions for defensive purposes, damaged host cells or foreign surfaces (for example, transplants and biomaterials) may trigger the cascade and cause clinical complications. For example, binding of natural antibodies (NAbs) to neoepitopes, released, for example, after hypoxia, or of auto-antibodies (AAbs) to auto-antigens may initiate the classical pathway (CP). Other damage-associated molecular patterns (DAMPs) can trigger the CP directly or invoke the lectin pathway (LP) via any of its pattern-recognition receptors, that is, mannose-binding lectin (MBL), ficolins (Fcns) or certain collectins (CLs). Either event leads to the formation of CP/LP C3 convertases (C4b2b), which in turn cleave C3 to generate the anaphylatoxin C3a and the opsonin C3b. Hydrolysis of C3 (depicted as C3*; also termed C3(H₂O)), which may either occur spontaneously (tick-over) or upon surface contact, provides a low-level activation of the alternative pathway (AP) by forming an initial AP C3 convertase (C3*Bb) with Factors B and D (FB and FD); thereby released C3b may assemble further AP C3 convertases (C3bBb), deposit directly on surfaces or, potentially, be recruited to select surfaces by the modulator properdin (FP). Surface-deposited C3b is the driving force of an amplification loop that leads to rapid opsonization with C3b. Increasing density of C3b favours the formation of CP/LP or AP C5 convertases (C4b2b3b and C3bBb3b, respectively) that cleave C5 to generate the potent chemoattractant and immune modulator of C5a and C5b, the initial component of the membrane attack complex (MAC), which may cause lysis, cell damage and/or signalling events. In a parallel breakdown pathway, complement regulators such as Factor H (FH), complement receptor 1 (CR1) or CD55 destabilize convertases and impair the amplification loop. Some regulators also serve as essential cofactors for the Factor I (FI)-mediated degradation of C3b to iC3b (that is, FH, CR1 and CD46) and C3dg (that is, CR1). These opsonin fragments modulate immune functions, including cell adhesion and activation, phagocytosis, cell signalling and stimulation of B cells and follicular dendritic cells. FH is the major fluid-phase regulator of the AP, whereas C4b-binding protein (C4BP) and C1 esterase inhibitor (C1-INH) control CP/LP activation, carboxypeptidase N (CPN) modulates anaphylatoxin activity and CD59 impairs MAC formation. Many complement proteins belong to major drug target classes, such as serine proteases or G protein-coupled receptors (GPCR), and/or engage in protein–protein interactions (PPIs) that may be modulated with therapeutic antibodies. MASP, mannose-binding lectin-associated serine protease; pFD, pro-FD. Top right image adapted with permission from REF., Science/AAAS.

Fig. 2 |. Examples of acute or transient complement-mediated disorders with currently evaluated treatment strategies.

a | Trauma-related and sepsis-related tissue damage are examples of complement involvement during severe inflammatory response syndrome. Microbial intruders (sepsis) or cell injury (trauma) lead to massive complement activation and stimulation of immune cells (for example, via the C5a anaphylatoxin). The resulting effector molecules, such as reactive oxygen and nitrogen species (ROS and NOS, respectively), cytokines or the membrane attack complex (MAC), cause additional tissue damage and fuel a vicious hyperinflammatory cycle that may lead to multiple organ failure. Whereas prevention of pattern recognition receptor (PRR)-mediated complement initiation by C1-esterase inhibitor (C1-INH) is currently evaluated in trauma, sepsis trials largely focus on blocking the C5a–C5aR1 signalling axis. b | Complement is a major contributor to transplant-related complications. Ischaemia–reperfusion (I/R) injury during transplantation (but also in stroke or myocardial infarction) triggers the exposure of damage-associated molecular patterns (DAMP) and/or neoantigens (Neo-Ag) that, upon reperfusion, are sensed by the PRR complexes of the lectin pathway and natural antibodies (NAb) via the classical pathway invoking a complement response. Similarly, mismatch with human leukocyte antigen (HL A) or ABO antigens after transplantation leads to pronounced classical pathway activation and may drive antibody-mediated rejection (AMR). In addition, these processes may contribute to immune cell activation and, consequently, to cell-mediated rejection. Therapeutic intervention at the initiation stage (using C1-INH), the amplification loop (using C3 inhibitors of the compstatin family) or at terminal effector pathways (using anti-C5 mAbs) are currently being evaluated.

Fig. 3 |. Examples of chronic complement-mediated disorders with currently evaluated treatment strategies.

a | Some autoimmune conditions show a pronounced complement involvement. In autoimmune haemolytic anaemia (AHIA) and cold agglutinin disease (CAD), recognition of red blood cells (RBCs) by autoantibodies (AAbs) activates the classical pathway (CP). Upon opsonization, formation of C3 and C5 convertases causes intravascular haemolysis (IVH). Clusters of erroneously glycosylated IgA can trigger the lectin pathway in IgA nephropathy (IgAN), whereas CP activation by anti-acetylcholine receptor (AChR) antibodies contributes to some forms of generalized myasthenia gravis (gMG). Finally, anti-neutrophil cytoplasmic antibodies (ANCA) may trigger the CP to generate C5a, which stimulates neutrophils and exacerbates the development of ANCA-associated vasculitis (ANCAV). All these conditions may contribute to localized tissue injury and inflammatory complications. Current trials focus on preventing lectin pathway initiation in IgAN (using anti-mannose-binding lectin-associated serine protease 2 (MASP2)), controlling CP activation and complement amplification in AIHA and CAD (using anti-C1s monoclonal antibodies (mAbs) or C3 inhibitors of the compstatin family) or C5aR1-mediated signalling in ANCAV (using C5aR1 antagonists). The anti-C5 mAb eculizumab is approved for the treatment of gMG. b | In paroxysmal nocturnal haemoglobinuria (PNH), the lack of glycosylphosphatidylinositol-anchored complement regulators on clonal populations of RBC predisposes to complement-mediated IVH. Whereas C5-targeted therapies effectively prevent IVH, they do not stop ongoing opsonization. This may potentially enable extravascular haemolysis (EVH), an unwanted effect that is expected to not occur with C3-targeted or convertase-targeted entities. Currently, compstatin analogues and small molecule Factor B (FB) and Factor D (FD) inhibitors are being evaluated for this purpose. c | Both C3 glomerulopathy (C3G) and atypical haemolytic syndrome (aHUS) are rare complement-mediated kidney disorders with diverse causes that are typically based on complement dysregulation. In C3G, the stabilization of soluble C3 convertases by C3 nephritic factor (C3Nef) often leads to C3 consumption with massive deposition of C3 fragments. Therapeutic options under consideration focus on preventing C3 convertase formation (FD inhibitors) or convertase-mediated C3 cleavage (compstatin and FB inhibitors). In aHUS, complement activation is initiated by certain hits; dysregulation by polymorphic surface regulators, the prevention of Factor H (FH) surface recognition by autoantibodies or the presence of gain-of-function components leads to activation of C5 with formation of C5a and membrane-attack complex (MAC) that cause tissue damage, inflammation and thrombotic microangiopathy (TMA), which by itself (for example, by release of haem from RBC) can act as a secondary hit for aHUS progression. Alongside the approved eculizumab, other C5-targeted entities and C5aR1 antagonists are evaluated for the treatment of aHUS. CR, complement receptor; PRR, pattern recognition receptor.