P020 Serum Ustekinumab and Anti-Ustekinumab Antibody: Analysis of Over 2000 Patient Results Using Lab Developed Electrochemiluminescent Immunoassays (ECLIA)

Abstract

BACKGROUND: Ustekinumab (UST) is a monoclonal interleukin-12 and -23 antagonist. To optimize efficacy, clinicians need to establish target concentrations based on studies elucidating UST pharmacokinetics and the relationship between serum UST and desired clinical and endoscopic outcomes. IM-UNITI data (n = 397) suggest a target UST trough concentration (TC) of >1 ug/mL at steady state (week 24) (1). Other smaller studies suggest week 8 and maintenance TC cutoffs of 2 and 4.5 ug/mL, respectively (2,3). In March 2018, therapeutic drug monitoring (TDM) to measure UST drug and anti-drug antibodies (ADAb) was launched. Here, 2098 ustekinumab patient results were analyzed. METHODS: Measurements of UST drug (free, ADAb-unbound) and anti-ustekinumab antibody (total including IgM and IgG subtypes) were performed by lab-developed ECLIA [2]. All ADAb positive samples are confirmed by a signal suppression test. Lower limits of quantitation are 0.1 ug/mL for UST and 40 ng/mL for ADAb. These ECLIAs were tested by Janssen R&D (Spring House, PA) for specificity, sensitivity, drug tolerance, accuracy, and precision and found to strongly agree with Janssen’s own R&D assays used in clinical trials (4). Clinical histories and blood collection timing are unknown. RESULTS: Of 2098 measured samples, 95.9% (2012) were ADAb-free and only 4.1% (86) had measurable anti-ustekinumab antibodies. In the absence of ADAb, UST concentrations ranged 0.1 to >32 ug/mL. Due to a highly sensitive lower limit of quantitation (0.1 ug/mL), only 38 (1.9%) had undetectable drug (<0.1). Of all ADAb-free samples, 9.2% were <1.0 and 24.6% were <2.0. Interestingly, half (50.4%) had UST less than 4.0. High UST (>10) occurred in 8.9% while 38.8% were 4.0–10. A small subset of patient samples (2.1%) had very high UST >20. Anti-ustekinumab antibodies ranged 42 to 9634 ng/mL. Only 3 of 2098 samples had ADAb > 1000; mean concomitant UST was undetectable. Most ADAb titers were 40–99 with a mean free UST of 4.5 ug/mL. CONCLUSION(S): Most samples received for UST monitoring were negative for anti-ustekinumab antibody and had UST <10 ug/mL. The therapeutic range for UST has yet to be firmly established. If a therapeutic cutoff of 1.0 ug/mL is used, then clinicians must be aware of the need for an adequately sensitive UST assay. Here, we found that 9.2% were <1 ug/mL. Using a cutoff of 2 ug/mL, 24.6% were below target. And if the threshold is 4.0 ug/mL, then the majority (50.4%) would be considered sub-therapeutic. Gastroenterologists are currently using TDM to try to optimize UST; therefore, better-established target concentrations for UST would be beneficial.