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. 2025 May;155(5):1557-1574.
doi: 10.1016/j.jaci.2025.01.025. Epub 2025 Jan 30.

Antibody-secreting cell repertoires hold high-affinity anti-rocuronium specificities that can induce anaphylaxis in vivo

Alice Dejoux  1 , Qianqian Zhu  2 , Adam Woolfe  3 , Ophélie Godon  4 , Sami Ellouze  3 , Guillaume Mottet  4 , Carlos Castrillon  4 , Caitlin Gillis  4 , Cyprien Pecalvel  5 , Christelle Ganneau  6 , Bruno Iannascoli  4 , Frédéric Lemoine  7 , Frederick Saul  8 , Patrick England  9 , Laurent L Reber  5 , Aurélie Gouel-Chéron  10 , Luc de Chaisemartin  11 , Ahmed Haouz  8 , Gaël A Millot  12 , Sylvie Bay  6 , Annabelle Gérard  3 , Friederike Jönsson  13 , Sylvie Chollet-Martin  11 , Pierre Bruhns  14
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Free article

Antibody-secreting cell repertoires hold high-affinity anti-rocuronium specificities that can induce anaphylaxis in vivo

Alice Dejoux et al. J Allergy Clin Immunol. 2025 May.
Free article

Abstract

Background: Neuromuscular blocking agents (NMBAs) are muscle relaxants used to assist mechanical ventilation but lead in 1 per 10,000 anesthesia cases to severe acute hypersensitivity reactions-that is, anaphylaxis. Incidences vary between types of NMBAs. Rocuronium, a widely used nondepolarizing aminosteroid NMBA, induces among the highest anaphylaxis rates. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies, but no such antibodies have ever been identified.

Objectives: We sought to identify rocuronium-specific antibody repertoires from plasma cells or plasmablasts of rocuronium-immunized mice to determine the affinities, structures, and anaphylactogenic potential of these antibodies for rocuronium.

Methods: We engrafted rocuronium onto carrier proteins allowing immunization of mice against rocuronium, screening for rocuronium-specific antibody responses, and sorting of rocuronium-specific plasma cells using droplet microfluids coupled to single-cell antibody gene (variable heavy chain [VH] and variable light chain [VL]) sequencing.

Results: The 2 different repertoires of >500 VH-VL pairs were oligoclonal, comprised 3 major clonal families, and displayed convergence. Expressed as human IgG1, these antibodies demonstrated subnanomolar affinities for rocuronium with families either monospecific for rocuronium or cross-reactive only for closely related NMBAs. Expressed as human IgE, they triggered human mast cell and basophil activation, and severe passive systemic anaphylaxis in mice humanized for the IgE receptor FcεRI. Cocrystal structures between rocuronium and antibody representatives of 3 different VH-VL families revealed distinct interaction modes, with the ammonium group involved systematically in the binding interface.

Conclusions: This work identifies the epitopes of antibody reactivity to rocuronium, demonstrates anaphylactogenic potential of anti-rocuronium IgE, and establishes the first mouse model of NMBA anaphylaxis.

Keywords: Antibodies; B cells; allergy; anaphylaxis; neuromuscular blocking agents; plasma cells; rocuronium; therapy.

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Conflict of interest statement

Disclosure statement Work in Bruhns’s laboratory was supported by the Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation pour la Recherche Médicale, Paris (Programme Equipe FRM grant EQU202203014631 to P.B.), Accélérateur de l’innovation de l’Institut Pasteur (grant rocuCEPT to P.B.), Agence Nationale de la Recherche (grants ANR-14-CE16-0011 “DROPmAbs,” ANR-16-CARN-0023-01 and ANR-21-CE15-0027 “CURAREP” to P.B.), European Research Council (ERC)–Seventh Framework Program (ERC-2013-CoG 616050 to P.B.) and INSERM International Research Program (grant ALLERGYMINE to P.B.). A.D. was supported by a doctoral fellowship from Sorbonne Université, followed by a fellowship from the Fondation pour la Recherche Médicale (grant FDT202304016860). Q.Z. received a PhD scholarship from the Chinese Science Council. A.G.C. was a recipient of a poste d’accueil in 2017 from Institut Pasteur–Assistance Publique des Hôpitaux de Paris, and was supported by a grant provided by INSERM, Société Française d’Anesthésie et de Réanimation (SFAR), and Société de Réanimation de Langue Française (SRLF) through the “Bourse de Recherche du Comité d’interface INSERM-SFAR-SRLF 2012” to A.G.C. C.M.G. was supported in part by a stipend from the Pasteur-Paris University international PhD program and by the Institut Carnot Pasteur Maladies Infectieuses. C.C. acknowledges financial support from CONCYTEC, Peru. P.B. benefited from an additional support from Assistance Publique-Hôpitaux de Paris through “Contrat Local d’Interface 2014” and Département Hospitalo-Universitaire FIRE. Disclosure of potential conflict of interest: P. Bruhns reports consulting fees from Regeneron Pharmaceuticals outside the present work. L. de Chaisemartin reports lecture fees from MSD France outside the present work. L. L. Reber reports grants and/or consulting fees from Neovacs, CEVA, Novartis, and Argenx outside the present work. A. Gérard is a cofounder and employee of Saber Bio SAS and former HiFiBiO Therapeutics SAS employee. Patents have been filed on some aspects of this work and future development of the platform, and the inventors may receive payments related to exploitation of these under their employer’s rewards to inventors scheme. The rest of the authors declare that they have no relevant conflicts of interest.