The Role of Complement in Chronic Inflammatory
This infographic has been organised and funded by Sanofi
Neurology
A rare, immune-mediated disease of the peripheral nervous system
• An autoimmune attack causes loss of the myelin sheath in the peripheral nerves and nerve roots, resulting in both proximal and distal motor weakness, sensory impairment, and loss of reflexes.1,2
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP)
References
EU/RUXO/NP/24/0009
Demyelinating Polyneuropathy
Pathogenesis
• Activation of the complement system by autoantibodies starts an enzymatic cascade that triggers damage to nerves via a number of mechanisms including macrophage-induced demyelination, membrane attack complex (MAC) formation and complement dependent damage by antibodies.3,4 The nodes of Ranvier and paranodal regions as well as the Schwann cells are particularly vulnerable, leading to axonal damage.3,4
1
The Role of Complement in the Nervous System
2
Complement Activation in CIDP9,13,17
Treatment Landscape and Emerging Targets in CIDP
3
Current first line Standard-of-Care (SoC) therapies for CIDP:
Intravenous (IV) & subcutaneous immunoglobulin (Ig)
Corticosteroids
Plasmapheresis
Among the majority of treatment responders, the response is often incomplete, and 30% of patients remain refractory to SoC.21 Existing therapies may have limited efficacy, may be burdensome, and have potential significant side effects.21-24
Ongoing research is exploring additional targets for the treatment of CIDP:
Complement inhibitors25-28
FcRn inhibitors29-32
B-cell depleting agents33-35
Progressive disability: Weakness that worsens over time may involve numbness and sensory impairment, contributing to fatigue and a reduced QoL.
Targeting the complement pathway cascade may prevent aberrant activation in CIDP by potentially blocking key inflammatory mechanisms underlying demyelination and axonal damage.25
Upstream inhibition: Targets early components of the classical pathway (C1 complex), reducing immune responses and macrophage activation.
Midstream inhibition: Targets components from both the classical and lectin pathways (C2, C3).
Downstream inhibition: Affects all complement pathways, targeting components like C5 and MAC formation.
Selective inhibition of the classical pathway may allow the alternative and lectin pathways to remain intact for host defense.26
4
POTENTIAL IMPACT Of COMPLEMENT INHIBITION IN CIDP
References
Abbreviations
MAT-GLB-2500594 - 1.0 - 04/2025
MAT-US-2503467 v1.0 - P Exp. Date: 04/03/2027
There are a number of global Phase II and III trials assessing emerging treatment options, including:
38. Sanofi. NCT06290128. https://clinicaltrials.gov/study/NCT06290128. Last accessed: 18 Sept 2024.
39. Chow T et al. Clin Transl Sci. 2023;16(4):673-85.
40. Nevo Y et al. CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy. Blood. 2013;121:129-35.
References
References
1. Lewis RA. In UpToDate, Pos TW (ed), Waltham MA, 2020.
2. Bowley MP, Chad DA. Handb Clin Neurol. 2019;161:241-68.
3. Dalakas MC. Biochimica et Biophysica Acta. 2015;1852:658-66.
4. Querol L et al. Nat Rev Neurol. 2017;13:533-47.
5. Magdalon J et al. Front Neurosci. 2020;14:23.
6. Ramaglia V et al. Mol Immunol. 2008;45(15):3865-77.
7. Sarma JV, Ward PA. Cell Tissue Res. 2011;343(1):227-35.
8. Thurman JM, Holers VM. J Immunol. 2006;176(3):1305-10.
9. Nikitin PA et al. J Immunol. 2019;202(4):1200-09.
10. Shih AR, Murali MR. Am J Hematol. 2015;90(12):1180-6.
11. Goldberg BS, Ackerman ME. Immunol Cell Biol. 2020;98(4):305-17.
12. Murphy K, Weaver C. Janeway’s Immunobiology (9th edition), Garland Science, 2016.
13. Querol L et al. Neurotherapeutics. 2022;19(3):864-73.
14. Köller H et al. N Engl J Med. 2005;352(13):1343-56.
15. Hays AP et al. J Neuroimmunol 1988;18:231-44.
16. Dalakas MC et al. Neurology 1980;30:864-7.
17. Quast I et al. Ann Clin Transl Neurol 2016;3:730-5.
18. Dejanovic B et al. Neuron. 2018;100(6):1322-36.
19. Hong S et al. Science. 2016;352(6286):712-6.
20. Vukojicic A et al. Cell Rep. 2019;29(10):3087-100.
21. Mair D et al. J Neurol Neurosurg Psychiatry. 2024;96(1):38-46.
22. Broers MC et al. Neuroepidemiology. 2019;52(3-4):161-72.
23. Yoon MS et al. Ther Adv Neurol Disord. 2011;4(3):193–200.
References
24. Cocito D et al. Eur J Neurol. 2010;17(2):289-94.
25. Rumsey JW et al. Adv Ther. 2022;5(6):2200030.
26. Querol L et al. J Peripher Nerv Syst. 2023;28(2):276-85
27. Querol L et al. AAN, Denver, April 13-18, 2024. Poster 008
28. Bioverativ. NCT04658472. Available at: https://clinicaltrials.gov/study/NCT04658472. Last accessed: 18 Sept 2024.
29. Immunovant Sciences. NCT05581199. Available at: https://clinicaltrials.gov/study/NCT05581199. Last accessed: 18 Sept 2024.
30. Argenx. NCT04281472. Available at: https://clinicaltrials.gov/study/NCT04281472. Last accessed: 18 Sept 2024.
31. Argenx. NCT04280718. Available at: https://clinicaltrials.gov/study/NCT04280718. Last accessed: 18 Sept 2024.
32. Janssen Research & Development. NCT05327114. https://clinicaltrials.gov/study/NCT05327114. Last accessed: 18 Sept 2024.
33. University of Kansas Medical Center. NCT04480450. https://clinicaltrials.gov/study/NCT04480450. Last accessed: 18 Sept 2024.
34. Istituto Clinico Humanitas. NCT05877040. https://clinicaltrials.gov/study/NCT05877040. Last accessed: 18 Sept 2024.
35. Nagoya University. NCT03864185. https://clinicaltrials.gov/study/NCT03864185. Last accessed: 18 Sept 2024.
36. Takeda. NCT05084053. https://clinicaltrials.gov/study/NCT05084053. Last accessed: 18 Sept 2024.
37. Sanofi. NCT06290141. https://clinicaltrials.gov/study/NCT06290141. Last accessed: 18 Sept 2024.
Abbreviations:
BNB: blood–nerve barrier; CIDP: chronic inflammatory demyelinating polyneuropathy; CR; complement receptor; CRP: C-reactive protein; FcRn: neonatal crystallizable fragment receptor; Ig: immunoglobulin; IV: intravenous; MAC: membrane attack complex; MBL: mannose-binding lectin; rHuPH20: recombinant human hyaluronidase; SCT: stem-cell transplatation; SoC: standard of care; sTCC: soluble terminal complement complex; TCR: T cell receptor. Medical writing assistance provided by Hannah Moir & created by Tim Uden, EMJ, London, UK.
R4CIDP and RF-2016-02361887, RECIPE, and jRCT2051210110 are currently assessing the efficacy and safety of B-cell depleting agents and IVIg33-36
IMVT-1401-2401, and CR109195 are currently assessing the efficacy and safety of FcRn inhibitors.29-32
VITALIZE and MOBILIZE are currently assessing the efficacy and safety of complement C1 inhibitor in those with CIDP with residual disability and refractory CIDP.37,38
Different Pathways of the Complement System8-12
1
Triggered by immune complexes (IgM, complement-fixing isotypes of IgG), CRP, serum amyloid P protein, and pentraxins8,10
Triggered mainly by binding of specific lectins circulating in the blood (collectins such as MBL and ficolins) to carbohydrates on the surface of microbial pathogens8,10
No specific initiating molecule. Instead, low-level constitutive activation of C3 occurs (“tick-over”)9,10
C3b facilitates opsonisation of antigens by binding to the surface of cells, including pathogens, tagging them for recognition and ingestion by phagocytic immune cells12
C5 cleavage leads to the formation of the MAC, which disrupts the cell membrane and induces cell lysis12
Infected tissue
C3a
C3a and C5a recruit phagocytic cells to the site of infection and promote inflammation12
enzymatic cleavage components12
Adapted from Murphy and Weaver.12 Created in BioRender.com EMJ (2025)
Inflammatory mediators12
The complement system plays an important role in the maintenance of the uninjured nerves, protecting them from infection and inflammation,5 and axonal loss (nerve damage) following an injury,6 removing damaged cells, and promoting regeneration.5-8
However, aberrant complement activation by autoantibodies, observed in autoimmune diseases such as CIDP, may contribute to various mechanisms inflicting damage to the myelin sheath.9,13
Increased permeability of the BNB allows humoral factors including complement to access peripheral nerve space13
Complement deposition on neural tissue may act as a trigger for macrophage-induced and demyelination13
Synapse loss18-20
Complement Activation in CIDP9,13,17
In CIDP, aberrant activation of the classical complement pathway by autoantibodies may contribute to demyelination and axonal damage.3,14
In people with CIDP who are treatment-naive, serum levels of complement component C5a and the cytolytic MAC are increased, which correlates to disease severity.17
Rare missense mutations in CD59, a cell surface glycoprotein that protects from complement hyperactivation, cause excessive activation of the complement system, causing a chronic demyelinating disease that resembles CIDP.40
In preclinical studies, inhibition of the complement classical pathway was shown to restore nerve function and limit disease progression.25 However, conclusions regarding efficacy and safety in humans cannot be made based on results from preclinical studies.
Created in BioRender.com EMJ (2025)
2
Ongoing Research Targets in CIDP
3
Inhibition of Complement May Deactivate the Classical Pathway
Adapted from Murphy and Weaver.12 Created in BioRender.com EMJ (2025)
*Investigational drug; † Refer to local marketing authorisation and prescribing information. Created in BioRender.com EMJ (2025)
IVIg36
