Academic Journal
Mapping of C5-Blocking Monoclonal Antibodies Reveals New C5 Inhibitory Epitopes and Novel Modes of C5 Inhibition.
| Τίτλος: | Mapping of C5-Blocking Monoclonal Antibodies Reveals New C5 Inhibitory Epitopes and Novel Modes of C5 Inhibition. |
|---|---|
| Συγγραφείς: | Cooke RS; UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, UK., Lee KY; UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, UK., Menzies GE; Molecular Biosciences Division, School of Biosciences, Cardiff University, Cardiff, UK., Mizuno M; Department of Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan., Morgan BP; UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, UK., Zelek WM; UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, UK. |
| Πηγή: | Immunology [Immunology] 2026 Nov; Vol. 179 (3), pp. 444-456. Date of Electronic Publication: 2026 Jul 27. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 0374672 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2567 (Electronic) Linking ISSN: 00192805 NLM ISO Abbreviation: Immunology Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Oxford : Blackwell Scientific Publications |
| Ιατρικοί όροι (MeSH): | Complement C5*/immunology , Complement C5*/antagonists & inhibitors , Complement C5*/metabolism , Antibodies, Monoclonal*/immunology , Antibodies, Monoclonal*/pharmacology , Epitopes*/immunology , Antibodies, Blocking*/immunology , Antibodies, Blocking*/pharmacology , Epitope Mapping*, Hemolysis/drug effects ; Antibodies, Monoclonal, Humanized/pharmacology ; Humans ; Animals ; Protein Binding |
| Περίληψη: | C5 inhibition is a proven therapeutic target with several monoclonal antibody (mAb) and small molecule drugs in the clinic. To explore alternative modes of inhibition, novel C5-blocking mAbs were generated and compared to therapeutic mAbs eculizumab and crovalimab. Blocking mAbs were selected using complement inhibition in haemolysis assays. C5 binding and competition between mAbs were tested by ELISA and surface plasmon resonance. Impact on C5 cleavage by CVF and native convertases was tested by western blotting of C5 fragments and ELISA for C5a release. Four novel C5-blocking mAbs were identified and shown to inhibit haemolysis with comparable efficacy to crovalimab and eculizumab. Competition assays identified four distinct function-blocking epitopes; mAb 7D4 and eculizumab competed for an α-chain epitope (epitope 1), while 10B6 and crovalimab competed for a β-chain epitope (epitope 2). mAbs 2B11 and 4G2 were not competitive with epitope 1/2 binders or each other, marking two distinct blocking α-chain epitopes (epitopes 3 and 4). Epitope 1 and epitope 2 binders blocked C5 convertase-mediated C5 cleavage and C5a release, while epitope 3 and epitope 4 binders permitted C5 cleavage, demonstrating distinct modes of inhibition. We identified four distinct C5 blocking epitopes; epitope 1 targeted by eculizumab and 7D4, epitope 2 targeted by crovalimab and 10B6 and epitopes 3 and 4 targeted by 2B11 and 4G2 respectively. Although all efficiently blocked haemolysis, epitope 3 and 4 binders permitted C5a release. We reveal (at least) four blocking epitopes on C5 and (at least) two distinct mechanisms of inhibition. (© 2026 The Author(s). Immunology published by John Wiley & Sons Ltd.) |
| References: | Blood. 2017 Feb 23;129(8):970-980. (PMID: 28028023) Immunobiology. 2018 Dec;223(12):744-749. (PMID: 30033110) Immunology. 2019 Aug;157(4):283-295. (PMID: 31120547) Eur J Immunol. 2024 Dec;54(12):e2350816. (PMID: 39263829) Lancet. 2024 Jan 27;403(10424):392-405. (PMID: 37979593) Nat Biotechnol. 2007 Nov;25(11):1256-64. (PMID: 17989688) Front Immunol. 2020 Dec 10;11:612402. (PMID: 33424866) Immunology. 2025 Nov;176(3):363-372. (PMID: 40523671) Mol Immunol. 1995 Nov;32(16):1183-95. (PMID: 8559143) Immunology. 2018 Nov;155(3):396-403. (PMID: 29981529) Mol Immunol. 2024 Jan;165:29-41. (PMID: 38142486) Am J Hematol. 2024 Sep;99(9):1667-1669. (PMID: 39023315) Drug Discov Today. 2024 Sep;29(9):104134. (PMID: 39111540) Am J Hematol. 2024 Sep;99(9):1757-1767. (PMID: 38924124) J Allergy Clin Immunol. 2025 Aug;156(2):308-310. (PMID: 40220910) J Neuroimmunol. 2000 Jun 26;105(2):124-30. (PMID: 10742554) Mol Immunol. 2016 Sep;77:126-31. (PMID: 27497837) Cell Rep. 2021 Apr 13;35(2):108995. (PMID: 33852847) Mol Immunol. 2019 Oct;114:341-352. (PMID: 31446305) N Engl J Med. 2014 Feb 13;370(7):632-9. (PMID: 24521109) Complement Inflamm. 1991;8(5-6):328-40. (PMID: 1724954) Transfus Med Rev. 2019 Oct;33(4):256-265. (PMID: 31703946) Nat Struct Mol Biol. 2016 May;23(5):378-86. (PMID: 27018802) Int J Mol Sci. 2024 Oct 30;25(21):. (PMID: 39519232) Blood. 2020 Mar 19;135(12):912-920. (PMID: 31978221) Front Immunol. 2023 Aug 09;14:1213920. (PMID: 37622108) Nat Immunol. 2008 Jul;9(7):753-60. (PMID: 18536718) Brain Behav Immun. 2025 Jul;127:287-302. (PMID: 40112933) J Biol Chem. 2023 Aug;299(8):104956. (PMID: 37356719) Immunobiology. 2025 Jul;230(4):153089. (PMID: 40544661) Sci Rep. 2016 Aug 11;6:31365. (PMID: 27509843) Sci Rep. 2017 Apr 24;7(1):1080. (PMID: 28439081) EMBO J. 2009 Aug 19;28(16):2469-78. (PMID: 19574954) Drugs. 2019 Feb;79(3):347-352. (PMID: 30767127) J Immunol. 2016 Jul 1;197(1):337-44. (PMID: 27194791) |
| Grant Information: | 526567 UK Research and Innovation; UK DRI-3002 UK Dementia Research Institute; 565 United States CU CSP VA; 565 Alzheimers Society |
| Contributed Indexing: | Keywords: C5; complement system; crovalimab; eculizumab; mechanism; membrane attack complex; therapeutic antibodies |
| Substance Nomenclature: | 0 (Complement C5) 0 (Antibodies, Monoclonal) 0 (Epitopes) 0 (Antibodies, Monoclonal, Humanized) A3ULP0F556 (eculizumab) 0 (Antibodies, Blocking) |
| Entry Date(s): | Date Created: 20260727 Date Completed: 20261005 Latest Revision: 20261007 |
| Update Code: | 20261007 |
| PubMed Central ID: | PMC13636134 |
| DOI: | 10.1111/imm.70180 |
| PMID: | 42509201 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1365-2567 |
|---|---|
| DOI: | 10.1111/imm.70180 |