Validating the positivity thresholds of drug-tolerant anti-infliximab and anti-adalimumab antibody assays

Abstract

Background: When used proactively, drug-tolerant anti-tumour necrosis factor (TNF) antibody assays provide early opportunity to suppress immunogenicity. Aim: To validate positivity thresholds of IDKmonitor drug-tolerant anti-infliximab and -adalimumab antibody assays. Methods: We applied positivity thresholds, defined by testing sera from 498 anti-TNF naive healthy adults, from the Exeter Ten Thousand study to data from our therapeutic drug monitoring (TDM) service and Personalised Anti-TNF Therapy in Crohn's disease (PANTS) cohort to explore associations with drug level and treatment outcomes. Results: The 80% one-sided lower confidence interval of the 99th centile concentration for anti-infliximab and –adalimumab antibodies were lower than the manufacturers threshold of 10 arbitrary units (AU)/mL; 9 and 6 AU/mL, respectively. Using these new thresholds in the TDM cohort, more adalimumab- than infliximab- (11.2% [814/7272] vs 3.1% [390/12 683] P < 0.0001) treated patients were reclassified as antibody-positive. Adalimumab drug concentrations in this reclassified group (median 8.1, interquartile range [IQR] 5.5-11.0 mg/L) were lower than those below the new threshold (<5AU/mL) (median 9.9, IQR 7.1-13.0 mg/L; P < 0.0001), but higher than at the manufacturer's threshold (10-29 AU/mL) (median 5.9 mg/L, IQR 3.5-8.7; P < 0.0001). No difference in infliximab drug concentration was observed using the new or manufacturer's positivity threshold (P = 0.11). In the PANTS cohort, patients with anti-adalimumab antibody concentrations at or above the new threshold were more likely to be in primary non-response (25/68 [37%] vs. 64/332 [19%], P = 0.0035), and non-remission at week 54 (51/62 [82%] vs. 168/279 [60%], P = 0.0011), than patients with anti-drug antibody concentrations in the group below the new threshold (0-5 AU/mL); this was not seen for anti-infliximab antibodies. Conclusion: Laboratories should derive antibody positivity thresholds for assays they use. For adalimumab, low-concentration anti-drug antibodies were associated with lower drug levels and treatment failure.