Complement-targeted therapeutics: Are we there yet, or just getting started?

Abstract

Therapeutic interventions in the complement system, a key immune-inflammatory mediator and contributor to a broad range of clinical conditions, have long been considered important yet challenging or even unfeasible to achieve. Almost 20 years ago, a spark was lit demonstrating the clinical and commercial viability of complement-targeted therapies. Since then, the field has experienced an impressive expansion of targeted indications and available treatment modalities. Currently, a dozen distinct complement-specific therapeutics covering several intervention points are available in the clinic, benefiting patients suffering from eight disorders, not counting numerous clinical trials and off-label uses. Observing this rapid rise of complement-targeted therapy from obscurity to mainstream with amazement, one might ask whether the peak of this development has now been reached or whether the field will continue marching on to new heights. This review looks at the milestones of complement drug discovery and development achieved so far, surveys the currently approved drug entities and indications, and ventures a glimpse into the future advancements yet to come.

Keywords: Complement system; Drug Discovery and Development; Therapeutics.

Figure 1

Complement activation and therapeutic intervention. (A) Simplified depiction of cell surface‐targeted complement activation. Targets of complement therapeutics that have been approved or authorized for use are marked by a capsule symbol. (B) General mechanisms of complement‐related indications with approved treatment options. Solid and dashed cell membranes depict sufficiently and insufficiently protected cell surfaces, respectively (due to polymorphic or missing regulators). Grey cells reflect dysfunctional and/or apoptotic cells, and orange flash symbols indicate tissue damage. (B) Timeline of complement‐targeted therapeutics in the clinic, showing drug approvals (top) and indication extension (bottom). Only officially approved complement‐specific drugs are shown, omitting C1 esterase inhibitor (C1‐INH) preparations, eculizumab biosimilars, and emergency use authorizations (Table 1; as of May 2024). Timeline number correspond to years between 2007 and 2024. AAV, ANCA‐associated vasculitis; Ab, antibody; AChR, acetylcholine receptor; aHUS, atypical hemolytic uremic syndrome; AMD, age‐related macular degeneration; ANCA, antineutrophil cytoplasmic antibody; AP, alternative pathway; AQP4, aquaporin‐4; BM, Bruch's membrane; C1‐INH, C1 esterase inhibitor; C3aR, C3a receptor; C5aR1, C5a receptor 1; CAD, cold agglutinin disease; CHAPLE, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein‐losing enteropathy; CL‐10/11, collectin‐10/11; CP, classical pathway; CR1‐4; complement receptor 1–4; EC, endothelial cell; Epi, epithelial cell; EVH, extravascular hemolysis; FB, factor B; FD, factor D; GA, geographic atrophy; GBM, glomerular basement membrane; gMG, generalized myasthenia gravis; GPCR, G protein‐coupled receptor; IVH, intravascular hemolysis; LP, lectin pathway; MAC, membrane‐attack complex; MASP, MBL‐associated serine protease; MBL, mannose‐binding lectin; MPO, myeloperoxidase; NET, neutrophil extracellular trap; NMOSD, neuromyelitis optica system disorders; PNH, paroxysmal nocturnal hemoglobinuria; RCA, regulators of complement activation; ROS, reactive oxygen species.

Figure 2

Structures of complement therapeutics that are currently approved (as of June 2024) or have been granted emergency use authorization. (A) Monoclonal antibodies as complement inhibitors. Individual domains of the depicted IgG structures are colored according to the species/isotype origin. Point mutations are marked by a star, independent of their functional implications. In the case of crovalimab, the stars may not reflect the true number and position of all modifications. (B) Peptide and aptamer drugs used as complement therapeutics. (C) Structures and properties of low‐molecular‐weight (LMW) complement inhibitors. For the assessment of Lipinski rule‐of‐5 properties [91], numbers in the table have been rounded; OH and NH groups were counted as HBD and the sum of N and O atoms as HBA; MW and log p‐values have been derived from PubChem (www.pubchem.org). FB, factor B; FD, factor D; HBA, hydrogen bond acceptor; HBD, hydrogen bond donor; IgG, immunoglobulin G; mAb, monoclonal antibody; MW, molecular weight; PEG, polyethylene glycol.