Rocuronium-specific antibodies drive perioperative anaphylaxis but can also function as reversal agents in preclinical models-Reference-Cited by-同舟云学术

Rocuronium-specific antibodies drive perioperative anaphylaxis but can also function as reversal agents in preclinical models

Published:2024-09-11 Issue:764 Volume:16 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Dejoux Alice¹²^ORCID,Zhu Qianqian¹³^ORCID,Ganneau Christelle⁴,Goff Odile Richard-Le¹^ORCID,Godon Ophélie¹^ORCID,Lemaitre Julien⁵^ORCID,Relouzat Francis⁵^ORCID,Huetz François¹^ORCID,Sokal Aurélien⁶⁷^ORCID,Vandenberghe Alexis⁶,Pecalvel Cyprien⁸^ORCID,Hunault Lise¹²,Derenne Thomas¹²^ORCID,Gillis Caitlin M.¹^ORCID,Iannascoli Bruno¹,Wang Yidan¹^ORCID,Rose Thierry⁹^ORCID,Mertens Christel¹⁰^ORCID,Nicaise-Roland Pascale¹¹^ORCID, ,England Patrick¹²,Mahévas Matthieu⁶^ORCID,de Chaisemartin Luc³¹¹^ORCID,Le Grand Roger⁵^ORCID,Letscher Hélène⁵^ORCID,Saul Frederick¹³,Pissis Cédric¹³,Haouz Ahmed¹³^ORCID,Reber Laurent L.⁸^ORCID,Chappert Pascal⁶^ORCID,Jönsson Friederike¹¹⁴^ORCID,Ebo Didier G.¹⁰^ORCID,Millot Gaël A.¹¹⁵^ORCID,Bay Sylvie⁴^ORCID,Chollet-Martin Sylvie³¹¹^ORCID,Gouel-Chéron Aurélie¹¹⁶¹⁷^ORCID,Bruhns Pierre¹¹⁸^ORCID,Mancardi David A.,Granger Vanessa,Longrois Dan,Montravers Philippe,Sauvan Caroline,Aubier Michel,Neukirch Catherine,Dib Fadia,Paugam-Burtz Catherine,Necib Skander,Keita-Meyer Hawa,Faitot Valentina,Mebazaa Alexandre,Le Dorze Matthieu,Cholley Bernard,Mantz Jean,Langeron Olivier,Roche Sabrine,Jacob Laurent,Plaud Benoit,Bresson Julie,Chahine Carole,Fischler Marc,Guinnepain Marie-Thérèse,Tubach Florence,Mignon Antoine

Affiliation:

1. Institut Pasteur, Université Paris Cité, INSERM UMR1222, Antibodies in Therapy and Pathology, 75015 Paris, France.

2. Sorbonne Université, Collège Doctoral, 75005 Paris, France.

3. Université Paris-Saclay, INSERM, Inflammation Microbiome Immunosurveillance, 91400 Orsay, France.

4. Institut Pasteur, Université Paris Cité, CNRS UMR3523, Chimie des Biomolécules, 75015 Paris, France.

5. Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases, 92260 Fontenay-aux-Roses and 94250 Le Kremlin-Bicêtre, France.

6. Institut Necker Enfants Malades, INSERM U1151/CNRS UMR 8253, Action thématique incitative sur programme-Avenir Team, Auto-Immune and Immune B cells, Université Paris Cité, Université Paris Est-Créteil, 94000 Créteil, France; INSERM U955, équipe 2. Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, 94000 Créteil, France.

7. Service de Médecine interne, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris Cité, 92110 Clichy, France.

8. Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, CNRS UMR5051, University Toulouse III, 31000 Toulouse, France.

9. Institut Pasteur, Université Paris Cité, INSERM UMR1224, Biologie Cellulaire des Lymphocytes, Ligue Nationale Contre le Cancer, Équipe Labellisée Ligue 2018, 75015 Paris, France.

10. Faculty of Medicine and Health Science, Department of Immunology-Allergology-Rheumatology, Antwerp University Hospital and the Infla-Med Center of Excellence, University of Antwerp, Antwerp, Belgium; Department of Immunology and Allergology, AZ Jan Palfijn Ghent, 9000 Ghent, Belgium.

11. Service d’immunologie Biologique, DMU BIOGEM, Hôpital Bichat, APHP, 75018, Paris, France.

12. Institut Pasteur, Université Paris Cité, CNRS UMR3528, Molecular Biophysics Core Facility, 75015 Paris, France.

13. Institut Pasteur, Université Paris Cité, CNRS UMR3528, Plate-forme Cristallographie-C2RT, 75015 Paris, France.

14. CNRS, F-75015 Paris, France.

15. Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, 75015 Paris, France.

16. Anaesthesiology and Critical Care Medicine Department, DMU Parabol, Bichat-Claude Bernard Hospital, AP-HP, 75018 Paris, France.

17. Université Paris Cité, 75010 Paris, France.

18. INSERM 1152, DHU FIRE, Labex Inflamex, Université Paris Diderot Paris 7, 75018 Paris, France.

Abstract

Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/scitranslmed.ado4463

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