Complement, a target for therapy in inflammatory and degenerative diseases

Abstract

The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.

Figure 1. Targets for inhibition in the complement pathway.

The figure shows a highly simplified view of the complement system and highlights the targets for pathway inhibition. Activation is triggered through classical (antibody) or lectin (sugar) pathways that rapidly converge to form a complement C3-cleaving enzyme (C3 convertase), C4b2a. The alternative pathway can be independently activated to generate its own C3 convertase (C3bBb) but, more importantly, amplifies activation regardless of trigger. C3 fragments, both soluble and surface-attached, engage specific receptors on expressing cells to mediate key activities. The C5 convertase, formed by the recruitment of an additional C3b into the C3 convertase, cleaves C5 to release a small fragment, C5a, which binds to receptors on expressing cells to mediate activation events. Formation of C5b initiates the membrane attack pathway; sequential recruitment of components C6, C7, C8 and C9 creates a pore in the target membrane – the membrane attack complex (MAC) – that can activate or kill the targeted cell. The complement system presents many targets for inhibition with drugs. In the activation pathways these include the initiating complexes and enzymes, the initiators of the alternative pathway loop and the C3 convertases. In the C3–C5 axis, potential targets include the individual components (for example, C3 and C5), the activation fragments (for example, C3a and C5a) and the C5 convertases. In the terminal pathway, agents might target individual components (such as C5, C6 or C7) or intermediates (such as C5b6 and C5b67), block the functional MAC pore or inhibit the downstream signalling events that mediate cell activation or destruction. PowerPoint slide

Figure 2. Controlling the alternative-pathway amplification loop.

The amplification (C3b feedback) loop is a positive-feedback cycle that consumes complement C3 to generate more enzyme and activation products; if unregulated, it cycles until all available C3 is consumed. Tight regulation is provided in the plasma by enzymes and cofactors that remove the C3 fragment C3b from the feedback cycle for breakdown into smaller fragments. As a consequence, the C3b feedback cycle normally operates at a very low rate (tickover). The balance between activation and regulation is disturbed in disease; a healthy balance can be restored by providing extra control (for example, increasing regulation, such as that provided by the complement regulatory protein Factor H (FH), thereby increasing 'feed out' from the amplification loop) or by preventing the formation of C3b in the feedback cycle (for example, by blocking convertase enzyme, thereby decreasing 'feed in' to the amplification loop). Agents that target amplification of complement can have major therapeutic effects. Ba, non-catalytic fragment of FB; C3b–FH, complex between C3b and FH; CR1, complement receptor type 1; iC3b–FH, complex between inactive C3b and FH. Adapted with permission from Ref. , Elsevier. PowerPoint slide

Figure 3. Progress of complement therapeutics towards clinical use.

The figure graphically illustrates a current 'snapshot' of the different areas of complement that are being targeted and the progress of the drugs — both marketed and en route to approval. It is a rapidly moving field and, inevitably, some compounds will progress, others will fail and new drugs will emerge to take their positions in the landscape in the coming months and years. One certainty is that this already crowded field will become much more so in the near future. Among the monoclonal antibodies, TNT003 and TNT009 (True North Therapeutics) target complement fragment C1s; OMS721 (Omeros) targets MBL-associated serine protease 2 (MASP2); Lampalizumab (Roche/Genentech) targets Factor D (FD), Bikaciomab (Novelmed) targets FB; IFX-1 (InflaRx) targets C5a; eculizumab (Soliris; Alexion Pharmaceuticals), LFG316 (Novartis), ALXN1210 and ALXN550 (Alexion) all target C5. Regenesance are developing an antibody that targets C6, and Novelmed are developing an antibody (NM9401) against properdin. Among the protein biologics, Berinert (CSL Behring), Ruconest (Salix Pharmaceuticals) and Cinryze (Shire Pharmaceuticals) are all C1INH preparations that target C1; AMY-201 (Amyndas) is a mini FH; TT30 (ALXN1102; Alexion) is a CR2–FH hybrid; TP10 (CDX-1135; Celldex Therapeutics) is a soluble form of complement receptor type 1 (CR1); Coversin (Volution Immuno Pharmaceuticals) is a C5-binding protein; Mirococept is a targeted CR1 fragment developed by AdProTech and currently in clinical trials led by King's College London; and the affibody SOBI002 (Swedish Orphan Biovitrum) targets C5 (programme recently terminated). Small-molecule inhibitors include CCX-168 (ChemoCentryx) and DF2593A (Dompé Pharmaceutical), which target C5aR; FD inhibitors from Achillion and Novartis; and a properdin inhibitor from Novelmed. Among the peptide-based therapeutics, Cp40 (Amyndas), APL-1 and APL-2 (Apellis Pharmaceuticals) are compstatin derivatives targeting C3; and RA101348 (RaPharma) is a C5 blocking peptide. Nucleic acid-based drugs include ARC1905 (Zimura; Ophthotech), a C5 aptamer; ALN-CC5 (Alnylam Pharmaceuticals), a C5 RNA interference (RNAi) molecule; and the Spiegelmers NOX-D19 to NOX-D21 (Noxxon Pharma), targeting C5a. Regenesance are developing a C6 antisense molecule. PowerPoint slide