Sa1248 TNF-Responsive Cellular Based Assay Reveals Neutralizing Capacity of Anti-Adalimumab Antibodies in Crohn's Disease and Ulcerative Colitis Patients

Abstract

Introduction: During infliximab(IFX) therapy for IBD anti-drug antibody formation can lead to loss of response(LOR) to the drug. Data for adalimumab is limited. Karmiris et al.1 demonstrated that adalimumab resulted in sustained clinical benefit in two thirds of Crohn's disease(CD) patients during 2 year follow-up. We performed additional analyses on this cohort using the homogeneous mobility shift assay(HMSA)2, focusing on the inter-relationship of serum concentrations of adalimumab, antibodies-to-adalimumab(ATA) and CRP. Methods: 536 prospectively collected serum samples were available from 148/168 patients in the Karmiris cohort for additional analysis. Serum adalimumab and ATA at pre-defined time points were measured using HMSA. Samples were classified as ATA negative, ATA detectable(non-zero ATA levels below the lower limit of quantitation, LLOQ of 1.7 U/ml) or ATA positive(ATA ≥ LLOQ). The LLOQ for adalimumab was ≥ 1.0 μg/ml. We studied the role of week 4 adalimumab levels on ATA formation with a Cox proportional hazards model of time-to-ATA vs. adalimumab. Repeated measures mixed regression modeling was performed to assess the independent effects of ATA and adalimumab on CRP. Results: ATA were positive(above LLOQ) in 20.2 % of patients (n = 30/148) after a median of 34 weeks(IQR 12.4 60.5 weeks). Samples with adalimumab in the lower two quartiles were more often ATA positive compared to samples in the 3rd and 4th adalimumab quartile(p LLOQ) were associated with lower median adalimumab levels than ATA negative samples(p 5 μg/ml(HR = 11.13, p = 0.0002). Regression modeling showed a negative correlation between CRP and adalimumab levels(p=0.0013) and a positive association with ATA(p=0.042). When the model was used to predict CRP one observation in the future, ATA was strongly associated with future CRP increase (p=0.002; median 7.8 weeks between samples; IQR 4.0 15.8), while adalimumab levels were not(p=0.176). Per-patient median CRP was significantly higher in patients who eventually failed adalimumab therapy (median 8.34 mg/L vs. 4.35 mg/L; p=0.026). Conclusion: Using HMSA, ATA were detected in 20% of patients in this cohort on adalimumab maintenance therapy, compared to 9% as previously reported2. Risk of ATA formation increased with lower early drug levels. Interestingly ATA was strongly associated with CRP in the future while drug levels were only informative of present CRP levels. These data suggest that early drug and antibody level monitoring and subsequent dose optimization would help prevent ATA and improve patient outcomes.