Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
J Gastroenterol Hepatol. 2019 Jul;34(7):1175-1181. doi: 10.1111/jgh.14584. Epub 2019 Jan 16.
The pivotal GEMINI trials reported low immunogenicity of vedolizumab. However, anti-vedolizumab antibodies (AVA) are frequently underestimated because most assays are not drug-tolerant and unable to detect antidrug antibodies while there is drug in the circulation. This study aimed to explore which antidrug antibody assay is best suited to detect AVA and investigated immunogenicity of vedolizumab in inflammatory bowel disease (IBD) patients discontinuing vedolizumab therapy.
A drug-tolerant affinity capture elution (ACE) assay was developed for the measurement of AVA in the presence of vedolizumab and compared with the previously established drug-resistant and drug-sensitive assays. Vedolizumab and AVA were measured at week 6, at the last infusion, and 12-20 weeks after treatment discontinuation in a cohort of 40 vedolizumab-treated IBD patients who stopped treatment due to primary non-response, loss of response, or adverse events.
The drug-tolerant ACE assay could detect AVA in samples that the drug-resistant and drug-sensitive assays were unable to. Using the drug-tolerant ACE assay, 3 (8%) out of 40 vedolizumab-treated IBD patients who discontinued therapy were AVA positive at week 6, whereas no AVA were detected at the last infusion nor after treatment discontinuation. Primary non-responders had numerically lower median vedolizumab concentrations at week 6 compared with patients with loss of response (20.3 vs 30.7 μg/mL, respectively, P = 0.0570).
Immunogenicity of vedolizumab is not the driving force of treatment failure, and AVA do not increase upon treatment discontinuation in vedolizumab-treated IBD patients. Underexposure during induction might partially be responsible for primary non-response.
GEMINI 关键性试验报道了维得利珠单抗的低免疫原性。然而，由于大多数检测方法不耐受药物，并且在药物循环时无法检测到抗药物抗体，因此经常低估了抗维得利珠单抗抗体（AVA）。本研究旨在探索哪种抗药物抗体检测最适合检测 AVA，并研究停用维得利珠单抗治疗的炎症性肠病（IBD）患者的维得利珠单抗免疫原性。
开发了一种药物耐受亲和力捕获洗脱（ACE）检测法，用于在存在维得利珠单抗的情况下测量 AVA，并与先前建立的耐药性和药物敏感性检测法进行比较。在因原发无应答、应答丧失或不良反应而停止治疗的 40 名接受维得利珠单抗治疗的 IBD 患者队列中，在第 6 周、最后一次输注时以及治疗停止后 12-20 周测量维得利珠单抗和 AVA。
药物耐受 ACE 检测法可检测到药物耐药性和药物敏感性检测法无法检测到的 AVA。使用药物耐受 ACE 检测法，在第 6 周时，3（8%）名停止治疗的接受维得利珠单抗治疗的 IBD 患者为 AVA 阳性，而在最后一次输注时和治疗停止后均未检测到 AVA。与应答丧失的患者相比，原发无应答者在第 6 周时的中位维得利珠单抗浓度略低（分别为 20.3 和 30.7μg/mL，P=0.0570）。
维得利珠单抗的免疫原性不是治疗失败的驱动因素，并且在接受维得利珠单抗治疗的 IBD 患者中，停药后 AVA 不会增加。诱导期的药物暴露不足可能部分导致原发无应答。
