New milestones ahead in complement-targeted therapy

Abstract

The complement system is a powerful effector arm of innate immunity that typically confers protection from microbial intruders and accumulating debris. In many clinical situations, however, the defensive functions of complement can turn against host cells and induce or exacerbate immune, inflammatory, and degenerative conditions. Although the value of inhibiting complement in a therapeutic context has long been recognized, bringing complement-targeted drugs into clinical use has proved challenging. This important milestone was finally reached a decade ago, yet the clinical availability of complement inhibitors has remained limited. Still, the positive long-term experience with complement drugs and their proven effectiveness in various diseases has reinvigorated interest and confidence in this approach. Indeed, a broad variety of clinical candidates that act at almost any level of the complement activation cascade are currently in clinical development, with several of them being evaluated in phase 2 and phase 3 trials. With antibody-related drugs dominating the panel of clinical candidates, the emergence of novel small-molecule, peptide, protein, and oligonucleotide-based inhibitors offers new options for drug targeting and administration. Whereas all the currently approved and many of the proposed indications for complement-targeted inhibitors belong to the rare disease spectrum, these drugs are increasingly being evaluated for more prevalent conditions. Fortunately, the growing experience from preclinical and clinical use of therapeutic complement inhibitors has enabled a more evidence-based assessment of suitable targets and rewarding indications as well as related technical and safety considerations. This review highlights recent concepts and developments in complement-targeted drug discovery, provides an overview of current and emerging treatment options, and discusses the new milestones ahead on the way to the next generation of clinically available complement therapeutics.

Keywords: Complement; Immune modulation; Inflammation; Therapeutics.

Figure 1. Targets and inhibitors for pharmacological intervention in the complement cascade

Simplified version of the complement cascade showing initiation on foreign/altered surfaces via the classical (CP), lectin (LP) and alternative (AP) pathways, generation of AP and CP/LP C3 convertases, amplification via the AP, and effector generation mainly via the AP and the terminal pathway. Some components, particularly the natural regulators/inhibitors, are not shown. Major effector functions in both physiological and pathophysiological contexts are listed in green and orange boxes, respectively (a yellow box signifies ambivalent function). Blue arrows represent conversion and/or assembly, green arrows enzymatic cleavage, and black dotted arrows signaling events. The various complement components are colored to signify major target classes as relevant for drug development (see legend). Inhibitors currently listed in the pipelines of pharmaceutical/biotech companies or known to be in clinical development are shown at their respective target, with red symbols to mark the inhibitor type (see legend); numbers refer to the inhibitor list in the upper right corner. Abbreviations: CL-11, collectin 11; CR, complement receptor; CRIg, CR of the immunoglobulin family; FB, factor B; Fcn, ficolins; FD, factor D; FP, properdin (factor P); MAC, membrane attack complex; MASP, MBL-associated serine protease; MBL, mannose-binding lectin.

Figure 2. Sources of complement inhibitors

Complement-modulating entities are currently derived from or synthesized as a broad spectrum of chemical classes, ranging from proteins and peptides (green, cyan) to oligonucleotides (orange) and small synthetic molecules (blue). The boxes provide typical examples of inhibitor classes resulting from each type of molecule. Abbreviations: PPI, protein-protein interaction; RNAi, RNA interference.

Figure 3. Considerations concerning the site and time-frame of clinical manifestations in complement-targeted therapy

Major examples of complement-related conditions are shown in the context of whether they primarily manifest systemically or locally (e.g., in a specific tissue or organ), and whether they occur as an acute, episodic, or chronic event. Abbreviations: aHUS, atypical hemolytic uremic syndrome; AIHA, autoimmune hemolytic anemia; AMD, age-related macular degeneration; AMR, antibody-mediated rejection; C3G, C3 glomerulopathy; CARPA, complement activation-related pseudoallergy; I/R, ischemia/reperfusion; PNH, paroxysmal nocturnal hemoglobinuria.