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.
- Dmards (biologic)
- autoimmune diseases
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Handling editor Josef S Smolen
Contributors KAvS, SK, POdH, NILD, FSvdB, AS, AEHB, SR, EMS, CAMK, MW and EB performed the experiments, analysed the data and helped revise the manuscript. GV, AEHB, WJ, SR, RIK, GW and TR designed the experiments. KAvS, SK, GV, WJ, SR, GW and TR contributed ideas. GV, AEHB, WJ, SR, RIK, FSvdB and GW helped write the manuscript. KAvS, GW and TR designed the study. KAvS and TR wrote the paper.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests GW reports grants from Pfizer during the conduct of the study; grants from Pfizer, payment for lectures from Pfizer, Abbvie and UCB outside the submitted work. TR reports grants from Pfizer during the conduct of the study; grants from Genmab, consultancy fees from Genmab and payment for lectures from Pfizer, Abbvie and Regeneron outside the submitted work. All other authors declare no competing financial interests.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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