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  • Review Article
  • Published:

The renaissance of complement therapeutics

Nature Reviews Nephrology volume 14, pages 26–47 (2018)Cite this article

Subjects

Key Points

  • Technological advances and the clinical experience with eculizumab have led to a new confidence in therapeutic strategies that target the complement system

  • Several candidate drugs aimed at a wide range of targets and indications have shown promising efficacy in preclinical studies and early clinical trials, and are now moving into late-stage clinical development

  • The number of potential indications for complement therapeutics, including kidney disorders, is growing owing to new genetic and molecular insights as well as clinical data

  • Given the pathological heterogeneity between and even within indications for complement-specific therapies, careful patient stratification will be essential to pave the way towards new therapeutic options

  • The field of complement drug discovery has already overcome several hurdles, and the growing clinical experience will help to assess the remaining and emerging challenges

Abstract

The increasing number of clinical conditions that involve a pathological contribution from the complement system — many of which affect the kidneys — has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond.

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Figure 1: Complement involvement in host defence, immune surveillance and disease processes.
Figure 2: Major mechanisms of the pathogenic involvement of complement in systemic and local disorders.
Figure 3: Therapeutic intervention in the complement cascade.
Figure 4: The complement drug development pipeline.

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Acknowledgements

The authors' work was supported by grants from the US National Institutes of Health (AI068730, AI030040) and the US National Science Foundation (grant No. 1423304), from the Swiss National Science Foundation (grant 31003A_176104) and by funding from the European Community's Seventh Framework Programme, under grant agreement number 602699 (DIREKT).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel, 4056, Switzerland

    Daniel Ricklin

  2. National Center for Scientific Research 'Demokritos', Patr. Gregoriou E & 27 Neapoleos Str, Agia Paraskevi, 15341, Athens, Greece

    Dimitrios C. Mastellos

  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 401 Stellar Chance, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Edimara S. Reis & John D. Lambris

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  1. Daniel Ricklin
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  2. Dimitrios C. Mastellos
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  4. John D. Lambris
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Contributions

All authors researched the data for the article, contributed to discussions of the content, wrote the text and reviewed or edited the article before submission.

Corresponding authors

Correspondence to Daniel Ricklin or John D. Lambris.

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Competing interests

J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors (including third-generation compstatin analogues such as AMY-101). 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 (4(1MeW)7W, also known as POT-4 and APL-1) and pegylated derivatives such as APL-2. D.R. has received speaker's honoraria from Alexion and Novartis. The other authors declare no competing interests.

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Glossary

Immunoediting

Complement-mediated immunoediting is a tightly regulated process by which complement tags (opsonizes) and subsequently spares or eliminates host cells, depending on the magnitude and quality of complement responses in distinct pathophysiological contexts. This process might involve other immune-related mechanisms and influences cell-specific or tissue-specific homeostatic and developmental pathways (for example, cell lineage commitment or turnover during development) as well as tissue regeneration and repair.

Synaptic pruning

The selective elimination of excess or unwanted synapses in the central nervous system during normal brain development and in age-related progressive neurological disorders. This process is mainly mediated by brain mononuclear phagocytic cells (that is, microglia) and reactive astrocytes.

Accommodation

In transplantation medicine, accommodation describes an acquired resistance of a transplanted organ to damage caused by complement, antibodies and other immune effector mechanisms.

Biosimilar

A biomedical product, such as a therapeutic antibody, that shares 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 protection of the original product expires.

Extravascular haemolysis

The process by which erythrocytes are eliminated through phagocytosis in the spleen, liver or bone marrow.

Pharmacodynamic breakthrough

A situation in which the inhibitory capacity of a complement-targeted therapeutic is exhausted owing to excessive complement activation, for example, as a result of acute infection or other triggers. Pharmacodynamic breakthrough might lead to a flare of disease symptoms despite continuous treatment.

Minibody

An engineered antibody fragment consisting of two single-chain variable fragments linked by a dimer of CH3 (and sometimes also CH2) domains of an antibody.

Aptamers

Short biopolymer sequences, typically of oligonucleotide (single-stranded RNA or DNA) or peptide origin, which are selected from a large, random sequence pool on the basis of their ability to bind a molecular target with high specificity.

Affibody

A small engineered protein based on the protein A scaffold from Staphylococcus aureus. Combinatorial variation of key residues in the scaffold enables the generation of affibody proteins that mimic antibodies by binding various targets with high affinity.

Macrocyclic peptide

Nonlinear peptides of natural or synthetic origin that form ring structures containing several peptide residues. Macrocyclic peptides often have distinct properties from their linear counterparts, and many are being developed as therapeutic inhibitors of protein–protein interactions.

Exosite

In an enzyme, an exosite is a functionally important area of the protein that is distinct and often distant from the active or catalytic site. Exosites might, for example, mediate the binding of substrates or cofactors and might constitute interesting targets for inhibitors of protein–protein interactions, such as antibodies.

Cytotopic drug

A drug that is targeted to and acts on a cell surface owing to a tethering moiety.

HexaBodies

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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Ricklin, D., Mastellos, D., Reis, E. et al. The renaissance of complement therapeutics. Nat Rev Nephrol 14, 26–47 (2018). https://doi.org/10.1038/nrneph.2017.156

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