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.
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We thank D. McClellan for editorial assistance. J.D.L. also thanks R. and S. Weaver for the generous endowment of his professorship. Given the broad scope of this review, we often refer to specialized review articles rather than primary literature, and we have only been able to include selected examples of the breadth of the transformative work in the field; we therefore want to thank all our colleagues who are not specifically cited for both their contributions and their understanding. We thank A. Sfyroera (National and Kapodistrian University of Athens) for selecting the ancient Greek quote about targeted therapies. This work was supported by grants from the US National Institutes of Health (AI068730; to J.D.L.) and from the Swiss National Science Foundation (31003A_176104; to D.R.). D.C.M. acknowledges support from project MIS 5002559, which is implemented under the “Action for the Strategic Development on the Research and Technological Sector”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co-financed by Greece and the European Union (European Regional Development Fund).
J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for therapeutic purposes. J.D.L. and D.R. are inventors of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals. J.D.L. is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (that is, 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives). D.C.M. declares no competing interests.
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- Pattern recognition receptors
A wide spectrum of soluble or membrane-bound proteins present on cells of the innate immune system that specifically recognize molecular signatures derived from the surface or interior of microbial cells, termed pathogen-associated molecular patterns, or distinct structures on artificial surfaces or altered host cells, termed damage-associated molecular patterns, to trigger a proinflammatory response that aims to respectively contain the microbial challenge or a maladaptive inflammatory response that may lead to tissue damage.
- Constrained peptides
A new class of peptide molecules whose supramolecular structure is constrained into a particular conformation via intramolecular covalent bonds that endow these peptides with biochemical and/or physicochemical properties amenable to drug development.
- RNA aptamers
Single-stranded RNA-based biopolymer sequences selected from a large, random sequence pool by virtue of their ability to bind a molecular target with high selectivity.
Biomedical products, such as a therapeutic antibody, that share a high degree of structural and functional similarity with a product that is already clinically approved. Similar to small-molecule generic drugs, biosimilars are typically introduced once the patent protecting the original medicinal product expires.
- Breakthrough haemolysis
The transient increase of markers of intravascular haemolysis (that is, elevated lactate dehydrogenase levels and decreased haemoglobin) in patients receiving treatment designed to abrogate intravascular haemolysis. Typically, breakthrough haemolysis is attributed either to pharmacokinetic or pharmacodynamic issues.
Engineered therapeutic antibodies with strong complement-mediated cytotoxic potential due to their increased propensity to form hexameric clusters on target surfaces such as cancer cells.
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Mastellos, D.C., Ricklin, D. & Lambris, J.D. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 18, 707–729 (2019). https://doi.org/10.1038/s41573-019-0031-6
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