TY - JOUR
T1 - Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies
AU - van Schie, Karin A.
AU - Kruithof, Simone
AU - Ooijevaar-de Heer, Pleuni
AU - Derksen, Ninotska I. L.
AU - van de Bovenkamp, Fleur S.
AU - Saris, Anno
AU - Vidarsson, Gestur
AU - Bentlage, Arthur E. H.
AU - Jiskoot, Wim
AU - Romeijn, Stefan
AU - Koning, Roman I.
AU - Bos, Erik
AU - Stork, Eva Maria
AU - Koeleman, Carolien A. M.
AU - Wuhrer, Manfred
AU - Wolbink, Gertjan
AU - Rispens, Theo
PY - 2018
Y1 - 2018
N2 - Objectives: Therapeutic antibodies can provoke an antidrug antibody (ADA) response, which can form soluble immune complexes with the drug in potentially high amounts. Nevertheless, ADA-associated adverse events are usually rare, although with notable exceptions including infliximab. The immune activating effects and the eventual fate of these 'anti-idiotype' complexes are poorly studied, hampering assessment of ADA-associated risk of adverse events. We investigated the in vitro formation and biological activities of ADA-drug anti-idiotype immune complexes using patient-derived monoclonal anti-infliximab antibodies. Methods: Size distribution and conformation of ADA-drug complexes were characterised by size-exclusion chromatography and electron microscopy. Internalisation of and immune activation by complexes of defined size was visualised with flow imaging, whole blood cell assay and C4b/c ELISA. Results: Size and conformation of immune complexes depended on the concentrations and ratio of drug and ADA; large complexes (>6 IgGs) formed only with high ADA titres. Macrophages efficiently internalised tetrameric and bigger complexes in vitro, but not dimers. Corroborating these results, ex vivo analysis of patient sera demonstrated only dimeric complexes in circulation. No activation of immune cells by anti-idiotype complexes was observed, and only very large complexes activated complement. Unlike Fc-linked hexamers, anti-idiotype hexamers did not activate complement, demonstrating that besides size, conformation governs immune complex potential for triggering effector functions. Conclusions: Anti-idiotype ADA-drug complexes generally have restricted immune activation capacity. Large, irregularly shaped complexes only form at high concentrations of both drug and ADA, as may be achieved during intravenous infusion of infliximab, explaining the rarity of serious ADA-associated adverse events.
AB - Objectives: Therapeutic antibodies can provoke an antidrug antibody (ADA) response, which can form soluble immune complexes with the drug in potentially high amounts. Nevertheless, ADA-associated adverse events are usually rare, although with notable exceptions including infliximab. The immune activating effects and the eventual fate of these 'anti-idiotype' complexes are poorly studied, hampering assessment of ADA-associated risk of adverse events. We investigated the in vitro formation and biological activities of ADA-drug anti-idiotype immune complexes using patient-derived monoclonal anti-infliximab antibodies. Methods: Size distribution and conformation of ADA-drug complexes were characterised by size-exclusion chromatography and electron microscopy. Internalisation of and immune activation by complexes of defined size was visualised with flow imaging, whole blood cell assay and C4b/c ELISA. Results: Size and conformation of immune complexes depended on the concentrations and ratio of drug and ADA; large complexes (>6 IgGs) formed only with high ADA titres. Macrophages efficiently internalised tetrameric and bigger complexes in vitro, but not dimers. Corroborating these results, ex vivo analysis of patient sera demonstrated only dimeric complexes in circulation. No activation of immune cells by anti-idiotype complexes was observed, and only very large complexes activated complement. Unlike Fc-linked hexamers, anti-idiotype hexamers did not activate complement, demonstrating that besides size, conformation governs immune complex potential for triggering effector functions. Conclusions: Anti-idiotype ADA-drug complexes generally have restricted immune activation capacity. Large, irregularly shaped complexes only form at high concentrations of both drug and ADA, as may be achieved during intravenous infusion of infliximab, explaining the rarity of serious ADA-associated adverse events.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85049200679&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29945923
U2 - https://doi.org/10.1136/annrheumdis-2018-213299
DO - https://doi.org/10.1136/annrheumdis-2018-213299
M3 - Article
C2 - 29945923
SN - 0003-4967
VL - 77
SP - 1471
EP - 1479
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
IS - 10
ER -