PMID- 38070782 OWN - NLM STAT- MEDLINE DCOM- 20231222 LR - 20231222 IS - 1879-0720 (Electronic) IS - 0928-0987 (Linking) VI - 192 DP - 2024 Jan 1 TI - Infliximab aggregates produced in severe and mild elevated temperature stress conditions induce an extended specific CD4 T-cell response. PG - 106670 LID - S0928-0987(23)00298-1 [pii] LID - 10.1016/j.ejps.2023.106670 [doi] AB - Aggregation has been widely described as a factor contributing to therapeutic antibody immunogenicity. Although production of high-affinity anti-drug antibodies depends on the activation of CD4 T lymphocytes, little is known about the T-cell response induced by antibody aggregates, especially for aggregates produced in mild conditions resulting from minor handling errors of vials. Large insoluble infliximab (IFX) aggregates produced in severe elevated temperature stress conditions have been previously shown to induce human monocyte-derived dendritic cell (moDC) maturation. We here showed that large IFX aggregates recruit in vitro a significantly higher number of CD4 T-cells compared to native IFX. Moreover, a larger array of T-cell epitopes encompassing the entire variable regions was evidenced compared to the native antibody. We then compared the responses of moDCs to different types of aggregates generated by submitting IFX to mild conditions of various times of incubation at an elevated temperature. Decreasing stress duration reduced aggregate size and quantity, and subsequently altered moDC activation. Of importance, IFX aggregates generated in mild conditions and not altering moDC phenotype generated an in vitro T-cell response with a higher frequency of CD4 T cells compared to native IFX. Moreover, cross-reactivity studies of aggregate-specific T cells showed that some T cells could recognize both native and aggregated IFX, while others responded only to IFX aggregates. Taken together, our results suggest that aggregation of antibodies in mild elevated temperature stress conditions is sufficient to alter moDC phenotype in a dose-dependent manner and to increase T-cell response. CI - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Nabhan, Myriam AU - Nabhan M AD - Universite Paris-Saclay, Inserm, Inflammation, Microbiome and Immunosurveillance, 91 400 Orsay, France; Universite Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LABEX LERMIT), 91400 Orsay, France. FAU - Meunier, Sylvain AU - Meunier S AD - Universite de Paris-Saclay, CEA, INRAE, Departement Medicaments et Technologies pour la Sante, SIMoS, 91191 Gif-sur-Yvette, France; Universite Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LABEX LERMIT), 91400 Orsay, France. FAU - Le-Minh, Victor AU - Le-Minh V AD - Universite Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 91 400 Orsay, France; Universite Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LABEX LERMIT), 91400 Orsay, France. FAU - Robin, Baptiste AU - Robin B AD - Universite Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 91 400 Orsay, France; Universite Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LABEX LERMIT), 91400 Orsay, France. FAU - de Bourayne, Marie AU - de Bourayne M AD - Universite de Paris-Saclay, CEA, INRAE, Departement Medicaments et Technologies pour la Sante, SIMoS, 91191 Gif-sur-Yvette, France; Universite Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LABEX LERMIT), 91400 Orsay, France. FAU - Smadja, Claire AU - Smadja C AD - Universite Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 91 400 Orsay, France; Universite Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LABEX LERMIT), 91400 Orsay, France. FAU - Maillere, Bernard AU - Maillere B AD - Universite de Paris-Saclay, CEA, INRAE, Departement Medicaments et Technologies pour la Sante, SIMoS, 91191 Gif-sur-Yvette, France; Universite Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LABEX LERMIT), 91400 Orsay, France. FAU - Pallardy, Marc AU - Pallardy M AD - Universite Paris-Saclay, Inserm, Inflammation, Microbiome and Immunosurveillance, 91 400 Orsay, France; Universite Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LABEX LERMIT), 91400 Orsay, France. FAU - Turbica, Isabelle AU - Turbica I AD - Universite Paris-Saclay, Inserm, Inflammation, Microbiome and Immunosurveillance, 91 400 Orsay, France; Universite Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LABEX LERMIT), 91400 Orsay, France. Electronic address: isabelle.turbica@universite-paris-saclay.fr. LA - eng PT - Journal Article DEP - 20231208 PL - Netherlands TA - Eur J Pharm Sci JT - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JID - 9317982 RN - B72HH48FLU (Infliximab) SB - IM MH - Humans MH - Infliximab/pharmacology MH - *CD4-Positive T-Lymphocytes/metabolism MH - Temperature MH - *Monocytes OTO - NOTNLM OT - Aggregation OT - Dendritic cells OT - Immunogenicity OT - Monoclonal antibody OT - T cells OT - T-cell repertoire COIS- Declaration of Competing Interest The authors state no conflict of interest. EDAT- 2023/12/10 06:43 MHDA- 2023/12/22 06:43 CRDT- 2023/12/09 19:28 PHST- 2023/06/27 00:00 [received] PHST- 2023/12/06 00:00 [revised] PHST- 2023/12/07 00:00 [accepted] PHST- 2023/12/22 06:43 [medline] PHST- 2023/12/10 06:43 [pubmed] PHST- 2023/12/09 19:28 [entrez] AID - S0928-0987(23)00298-1 [pii] AID - 10.1016/j.ejps.2023.106670 [doi] PST - ppublish SO - Eur J Pharm Sci. 2024 Jan 1;192:106670. doi: 10.1016/j.ejps.2023.106670. Epub 2023 Dec 8.