Reactome | C5 binds C5 inhibitors

C5 binds C5 inhibitors

Stable Identifier

R-HSA-9691621

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region

ReviewStatus

5/5

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Activation of the complement system significantly contributes to the pathogenesis of numerous acute and chronic diseases. Monoclonal antibodies (mAbs) that recognize the human complement protein C5 have been shown to effectively block C5 cleavage, thereby preventing the generation of pro-inflammatory complement components (Thomas et al. 1996, review Horiuchi & Tsukamoto 2016). The mAb eculizumab was the first therapeutic for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (Rother et al. 2007). Ravulizumab, also used to treat PNH, was engineered from eculizumab to have an inherently longer circulating half-life so as to extend dosing intervals (Sheridan et al. 2018). Crovalimab is another long-acting anti-C5 monoclonal antibody developed for the treatment of PNH, offering an alternative to both ravulizumab and eculizumab. Unlike these antibodies, crovalimab binds a distinct epitope located on the β-chain of C5 and remains effective in individuals with C5 polymorphisms. Crovalimab is designed to dissociate from C5 in acidic endosomes in a pH-dependent manner, allowing the antibody to be recycled and sustain complement inhibition. Additionally, crovalimab employs isoelectric point engineering to enhance uptake and clearance of C5 at lower doses (Sampei et al. 2018; Cosson et al. 2025; reviewed by Röth et al. 2024). Tesidolumab is an investigational mAb targeting complement C5, inhibiting terminal complement activation. Zilucoplan is a small macrocyclic peptide that binds to C5 with high affinity and specificity. It is being investigated for the treatment of myasthenia gravis (MG), a rare autoimmune disease (Howard et al. 2020). Pozelimab is a monoclonal antibody designed to block the activity of C5 in patients with CHAPLE disease, a rare genetic disorder caused by CD55 deficiency and characterized by excessive complement activation, angiopathic thrombosis, and protein-losing enteropathy (Latuszek et al. 2020; Lin et al., 2024). Additionally, avacincaptad pegol, a pegylated RNA aptamer, selectively binds complement component C5, preventing its cleavage into C5a and C5b. By inhibiting C5 activation, it may help treat geographic atrophy (GA) secondary to age-related macular degeneration (AMD) (reviewed by Danzig et al. 2024).

Literature References

PubMed ID	Title	Journal	Year
39073397	C5 inhibitor avacincaptad pegol treatment for geographic atrophy: A comprehensive review Danzig, CJ, Khanani, AM, Loewenstein, A	Immunotherapy	2024
32384086	Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5 Latuszek, A, Liu, Y, Olsen, O, Foster, R, Cao, M, Lovric, I, Yuan, M, Liu, N, Chen, H, Zhang, Q, Xiao, H, Springer, C, Ehrlich, G, Kamat, V, Rafique, A, Hu, Y, Krueger, P, Huang, T, Poueymirou, W, Babb, R, Rosconi, MP, Retter, MW, Chen, G, Morton, L, Zambrowicz, B, Cao, J, Romano, C, Olson, WC	PLoS One	2020
17989688	Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria Rother, RP, Rollins, SA, Mojcik, CF, Brodsky, RA, Bell, L	Nat. Biotechnol.	2007
9171898	Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv Thomas, TC, Rollins, SA, Rother, RP, Giannoni, MA, Hartman, SL, Elliott, EA, Nye, SH, Matis, LA, Squinto, SP, Evans, MJ	Mol. Immunol.	1996
29649283	Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action Sheridan, D, Yu, ZX, Zhang, Y, Patel, R, Sun, F, Lasaro, MA, Bouchard, K, Andrien, B, Marozsan, A, Wang, Y, Tamburini, P	PLoS ONE	2018
39620653	Crovalimab in the paroxysmal nocturnal hemoglobinuria treatment landscape Röth, A, Kulasekararaj, AG, Scheinberg, P, Nishimura, JI	Immunotherapy	2024
32065623	Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial Howard, JF, Howard, JF, Nowak, RJ, Nowak, RJ, Wolfe, GI, Wolfe, GI, Freimer, ML, Vu, TH, Hinton, JL, Hinton, JL, Benatar, M, Duda, PW, Duda, PW, MacDougall, JE, Farzaneh-Far, R, Farzaneh-Far, R, Kaminski, HJ, Kaminski, HJ, Zilucoplan MG Study Group, -, Zilucoplan MG Study Group, -, Barohn, R, Dimachkie, M, Pasnoor, M, Farmakidis, C, Liu, T, Colgan, S, Benatar, MG, Bertorini, T, Pillai, R, Henegar, R, Bromberg, M, Gibson, S, Janecki, T, Freimer, M, Elsheikh, B, Matisak, P, Genge, A, Guidon, A, David, W, Habib, AA, Mathew, V, Mozaffar, T, Hewitt, W, Barnett, D, Sullivan, P, Ho, D, Traub, RE, Chopra, M, Aly, R, Bayat, E, Abu-Rub, M, Khan, S, Lange, D, Holzberg, S, Khatri, B, Lindman, E, Olapo, T, Sershon, LM, Lisak, RP, Bernitsas, E, Jia, K, Malik, R, Lewis-Collins, TD, Nicolle, M, Sharma, A, Roy, B, Nye, J, Pulley, M, Berger, A, Shabbir, Y, Sachdev, A, Patterson, K, Siddiqi, Z, Sivak, M, Bratton, J, Small, G, Kohli, A, Fetter, M, Vu, T, Lam, L, Harvey, B, Silvestri, N, Patrick, K, Zakalik, K, MacDougall, J, Pontius, A, Hoarty, M	JAMA Neurol	2020