戈利木单抗的免疫原性及其在溃疡性结肠炎患者中的临床相关性。
Immunogenicity of Golimumab and its Clinical Relevance in Patients With Ulcerative Colitis.
机构信息
Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
GlaxoSmithKline, Collegeville, Pennsylvania, USA.
出版信息
Inflamm Bowel Dis. 2019 Aug 20;25(9):1532-1540. doi: 10.1093/ibd/izz003.
BACKGROUND
Antidrug antibody (ADA) detection with standard bridging enzyme immunoassays (EIA) can yield false-negative results or underestimate titers through drug interference. A more sensitive assay was needed to determine clinical impact of antigolimumab antibodies.
METHODS
A high-sensitivity, drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original EIA, and samples from induction/maintenance studies in golimumab-treated patients with ulcerative colitis were analyzed for ADAs using both methods. Immunogenicity results were compared, and pharmacokinetic, efficacy, and safety associations were evaluated.
RESULTS
An 8-fold increase in ADA-positive patients (21.8% DT-EIA vs 2.8% EIA) reflected DT-EIA improved sensitivity and drug tolerance. Most newly detected ADA-positive patients (using DT-EIA) had low antibody titers, whereas most with high antibody titers were ADA-positive with original EIA. With DT-EIA, week 44 median trough serum golimumab concentrations among ADA-positive patients were approximately half vs ADA-negative (0.51 vs 0.85 µg/mL [50 mg q4w]; 0.85 vs 1.60 µg/mL [100 mg q4w]). Antidrug antibody impact on golimumab concentrations was more notable at titers ≥1:100. During induction, ADAs had no notable impact on efficacy. During maintenance, proportions of patients maintaining clinical response through week 54 were lower using DT-EIA: 38.1% ADA-positive and 52.8% ADA-negative. Antidrug antibody status had no impact on injection-site reaction incidence.
CONCLUSIONS
A more sensitive DT-EIA identified higher proportions of ADA-positive patients. A trend of decreasing drug concentrations with increasing ADA titers was observed. Pharmacokinetic impact was better elucidated with DT-EIA. Although development of ADA did not preclude efficacy, a trend toward decreased efficacy in ADA-positive vs ADA-negative patients was observed during maintenance treatment. Antidrug antibody status did not impact safety.
背景
使用标准的桥接酶免疫分析（EIA）检测抗药物抗体（ADA）可能会因药物干扰而产生假阴性结果或低估滴度。需要更灵敏的检测方法来确定抗戈利木单抗抗体的临床影响。
方法
开发了一种高灵敏度、耐药物的 EIA（DT-EIA），并与原始 EIA 进行了交叉验证，然后使用这两种方法分析了接受戈利木单抗治疗溃疡性结肠炎的诱导/维持研究中的样本中的 ADA。比较了免疫原性结果，并评估了药代动力学、疗效和安全性关联。
结果
ADA 阳性患者的比例增加了 8 倍（21.8% DT-EIA 与 2.8% EIA），这反映了 DT-EIA 提高了灵敏度和药物耐受性。大多数新检测到的 ADA 阳性患者（使用 DT-EIA）的抗体滴度较低，而大多数高抗体滴度的患者在原始 EIA 中均为 ADA 阳性。在 DT-EIA 中，ADA 阳性患者的第 44 周谷血清戈利木单抗浓度约为 ADA 阴性患者的一半（0.51 对 0.85 µg/mL [50 mg q4w]；0.85 对 1.60 µg/mL [100 mg q4w]）。在抗体滴度≥1:100 时，ADA 对戈利木单抗浓度的影响更为显著。在诱导期，ADA 对疗效没有显著影响。在维持期，使用 DT-EIA 至第 54 周时，保持临床反应的患者比例较低：ADA 阳性患者为 38.1%，ADA 阴性患者为 52.8%。ADA 状态对注射部位反应发生率没有影响。
结论
更灵敏的 DT-EIA 鉴定出更高比例的 ADA 阳性患者。观察到随着 ADA 滴度的增加，药物浓度呈下降趋势。DT-EIA 更好地阐明了药代动力学的影响。尽管 ADA 的产生并没有排除疗效，但在维持治疗中，ADA 阳性患者与 ADA 阴性患者的疗效呈下降趋势。ADA 状态对安全性没有影响。
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