Friend or foe: assessing the value of animal models for facilitating clinical breakthroughs in complement research
Felix Poppelaars, … , V. Michael Holers, Joshua M. Thurman
Felix Poppelaars, … , V. Michael Holers, Joshua M. Thurman
Published June 16, 2025
Citation Information: J Clin Invest. 2025;135(12):e188347. https://doi.org/10.1172/JCI188347.
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Friend or foe: assessing the value of animal models for facilitating clinical breakthroughs in complement research

Abstract

Animal experiments have long been a cornerstone of advancements in biomedical research, particularly in developing novel therapeutic strategies for inflammatory and autoimmune diseases. However, these historically important approaches are now facing growing scrutiny for ethical reasons, concerns about translational limitations to human biology, and the rising availability of animal-free research methods. This shift raises a critical question: How relevant and effective are animal models for driving future advancements in today’s research landscape? This Review aims to explore this question within the field of biomedical research on the complement system, critically evaluating the contribution of animal models to the recent advancements and clinical successes of complement-targeted therapies. Specifically, we assess areas where animal studies have been indispensable for elucidating disease mechanisms and conducting preclinical evaluations, alongside instances where findings from animal models failed to translate successfully to human trials. Furthermore, we discuss similarities and differences in the complement system between animals and humans and explore innovations in animal research designed to improve translatability to human biology. By assessing the contributions of animal studies to complement therapeutics, this Review aims to provide insights into animal models’ strengths, limitations, and evolving role in complement research.

Authors

Felix Poppelaars, V. Michael Holers, Joshua M. Thurman

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Figure 1

Conservation of structure and function of C3 across species.

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Conservation of structure and function of C3 across species. (A) C3 is t...
(A) C3 is the central and most abundant circulating complement protein, forming the pivotal convergence point of all pathways. (B) Phylogenetic tree illustrating the early emergence of C3-like genes in primitive invertebrates. (C) Human C3 protein (UniProt Knowledgebase [UniProtKB]: P01024) exhibits significant homology with other animals, including mouse (UniProtKB: P01027), rat (UniProtKB: P01026), guinea pig (UniProtKB: P12387), pig (UniProtKB: P01025), and cynomolgus monkey (UniProtKB: A0A2K6D5R0). Percentages represent amino acid identity shared with human C3 and were obtained using the Align function on UniProt. (D) Human C3 consists of eight macroglobulin domains (MG1–MG8); an ANA domain; a linker (LNK) domain; a C1r/s, Uegf, B (CUB) domain; a TED; and a C345C domain. Structure of human C3 adapted from Zarantonello et al. with permission (368). Moreover, functional characteristics of C3 are conserved even in the most primitive invertebrates: (i) Cleavage of C3 removes the ANA domain (forming C3a) and induces conformational changes (forming C3b), exposing the reactive TED that enables covalent binding to surfaces. (ii) C3a is an ANA that can bind to its receptor (C3aR), leading to pro- and antiinflammatory effects, and is expressed in most species. (iii) Once formed, C3b can interact with Factor B, properdin, and various complement regulators. Factor B binding initiates formation of C3-convertases, which cleaves additional C3 into C3b, thereby creating an amplification loop. Binding of FH, MCP, DAF, and CR1 mediates C3-convertases’ deactivation (via disruption of the C3b–Bb interaction) or degradation (via proteolytic cleavage of C3b). (iv) C3 contains two highly conserved cleavage sites for Factor I (FI), which, in the presence of cofactors such as FH, MCP, or CR1, inhibit further activation and cleave C3. The first cleavage by FI releases C3f, forming inactivated C3b (iC3b). A second cleavage releases C3c from the target-bound C3dg fragment. C3 fragments can still exert functional consequences via interaction with receptors.