Johanna Sigaux1, Moustafa Hamze2, Claire Daien3, Jacques Morel3, Roman Krzysiek4, Marc Pallardy5, Bernard Maillere2, Xavier Mariette1, Corinne Miceli-Richard6. 1. Service de rhumatologie, hôpital de Bicêtre, hôpitaux universitaires Paris Sud, Assistance publique-Hôpitaux de Paris, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France; Inserm U1184, université Paris Sud, 91400 Orsay, France; Labex LERMIT, 94270 Le Kremlin-Bicêtre, France. 2. CEA, iBiTecS, service d'ingénierie moléculaire des protéines (SIMOPRO), Labex LERMIT, Labex VRI, 91191 Gif-sur-Yvette, France. 3. Département de rhumatologie, CHU Lapeyronie, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex, France; Université de Montpellier, 39, rue Université, 34295 Montpellier cedex, France. 4. Laboratoire d'immunologie, hôpitaux universitaires Paris Sud, Assistance publique-Hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France; UMR 996, 92140 Clamart, France; Labex LERMIT, 92140 Clamart, France. 5. UMR996, faculté de pharmacie, 92290 Châtenay-Malabry, France. 6. Service de rhumatologie, hôpital de Bicêtre, hôpitaux universitaires Paris Sud, Assistance publique-Hôpitaux de Paris, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France; Inserm U1184, université Paris Sud, 91400 Orsay, France; Labex LERMIT, 94270 Le Kremlin-Bicêtre, France. Electronic address: corinne.miceli@aphp.fr.
Abstract
OBJECTIVE: The immunogenicity of tocilizumab (TCZ) has been poorly studied. We assessed the immunogenicity of TCZ and serum TCZ trough levels in rheumatoid arthritis (RA) patients and the preexisting TCZ-specific CD4+ T cell repertoire in healthy controls. METHODS: Anti-drug antibodies (ADAs) to TCZ and serum TCZ trough levels in RA patients were assessed at different times by ELISA. Frequencies of naive anti-TCZ CD4+ precursors were studied in healthy controls. RESULTS: In total, 91 samples from 40 RA patients were analyzed: 21 patients within the first 6 months after treatment initiation and 19 during follow-up after a mean TCZ treatment duration of 21±13 months. None of the 91 samples showed persistent ADAs to TCZ. Only 3 RA patients showed transient and low titers of anti-TCZ ADAs. Serum TCZ trough levels were associated with neither patient characteristics (gender, body mass index) nor disease activity and were identical for patients with and without co-treatment with methotrexate. Three of 9 healthy donors showed preexisting TZC-specific CD4+ T cells at a low level. CONCLUSION: Serum TCZ trough levels were not affected by patient characteristics. The occurrence of ADAs to TCZ was a rare event. Because healthy donors show the same frequency of naive TCZ-specific and infliximab-specific CD4+ T cell precursors, the low prevalence of ADAs to TCZ might result from interleukin-6 blockade.
OBJECTIVE: The immunogenicity of tocilizumab (TCZ) has been poorly studied. We assessed the immunogenicity of TCZ and serum TCZ trough levels in rheumatoid arthritis (RA) patients and the preexisting TCZ-specific CD4+ T cell repertoire in healthy controls. METHODS: Anti-drug antibodies (ADAs) to TCZ and serum TCZ trough levels in RApatients were assessed at different times by ELISA. Frequencies of naive anti-TCZ CD4+ precursors were studied in healthy controls. RESULTS: In total, 91 samples from 40 RApatients were analyzed: 21 patients within the first 6 months after treatment initiation and 19 during follow-up after a mean TCZ treatment duration of 21±13 months. None of the 91 samples showed persistent ADAs to TCZ. Only 3 RApatients showed transient and low titers of anti-TCZADAs. Serum TCZ trough levels were associated with neither patient characteristics (gender, body mass index) nor disease activity and were identical for patients with and without co-treatment with methotrexate. Three of 9 healthy donors showed preexisting TZC-specific CD4+ T cells at a low level. CONCLUSION: Serum TCZ trough levels were not affected by patient characteristics. The occurrence of ADAs to TCZ was a rare event. Because healthy donors show the same frequency of naive TCZ-specific and infliximab-specific CD4+ T cell precursors, the low prevalence of ADAs to TCZ might result from interleukin-6 blockade.
Authors: Laura Magill; Marsilio Adriani; Véronique Berthou; Keguan Chen; Aude Gleizes; Salima Hacein-Bey-Abina; Agnes Hincelin-Mery; Xavier Mariette; Marc Pallardy; Sebastian Spindeldreher; Natacha Szely; David A Isenberg; Jessica J Manson; Elizabeth C Jury; Claudia Mauri Journal: Front Immunol Date: 2018-12-05 Impact factor: 7.561
Authors: Maurizio Benucci; Valentina Grossi; Mariangela Manfredi; Arianna Damiani; Maria Infantino; Paolo Moscato; Luigi Cinquanta; Elisa Gremese; Barbara Tolusso; Luca Petricca; Anna Laura Fedele; Stefano Alivernini; Fabiola Atzeni; Giovanni Minisola; Roberto Verna Journal: Ann Lab Med Date: 2020-03 Impact factor: 3.464