Abstract
IntroductionAnti-drug antibodies can affect biopharmaceutical pharmacokinetics by increasing or decreasing drug clearance. Drug-tolerant (total), unlike drug-sensitive (free), antibody assays permit antibodies to be measured in the presence of drug.We aimed to confirm the positivity threshold of our total anti-tumour necrosis factor (TNF) antibody ELISA assays in healthy volunteers and to use this threshold to report the prevalence of clearing and transient antibodies in patients treated with infliximab and adalimumab.MethodsSerum was obtained from 498 anti-TNF-naïve healthy adults recruited to the Exeter 10,000 study and tested for total anti-drug antibodies to infliximab and adalimumab. We used bootstrapping to calculate the 80% one-sided lower confidence interval [CI] of the 99th centile recommended by the FDA to define assay thresholds.We used paired drug and anti-drug antibody levels derived from our national therapeutic drug monitoring service to report the distribution of clearing (antibody positive, drug negative) vs non-clearing (antibody positive, drug positive) antibodies. In patients with at least two test results, antibodies were classified as transient (single positive test with subsequent negative test) or persistent (at least two positive tests).ResultsThe 80% one-sided lower CI of the 99th centile titre for total anti-drug antibody to infliximab and adalimumab were 8.7 AU/mL and 5.9 AU/mL, respectively.Using these thresholds, at the time of last testing, of 7,428 and 4,043 patients treated with infliximab and adalimumab; 21.1% and 8.3% had clearing antibodies and 27.9% and 20.0% had non-clearing antibodies, to infliximab and adalimumab, respectively.Amongst patients with at least two tests, most developed persistent antibodies. Irrespective of anti-TNF drug, or threshold used, less than 10% patients developed transient antibodies.Across both our national TDM cohort and the PANTS study, there were significant associations between anti-drug antibody and drug levels (figure 1). In PANTS, higher anti-drug antibody levels were associated with poorer outcomes at weeks 14 and 54.Abstract P118 Figure 1Relationship between adalimumab drug and anti-drug antibody levels in national TDM cohortConclusionsWe report lower positivity thresholds for the IDKmonitor® total anti-TNF antibody ELISA assays than the manufacturer, in particular, for adalimumab. Transient antibody formation is uncommon: most patients develop persistent anti-drug antibodies that lead to drug clearance.