开发一种 C1q 固定化（Cim）测定法来测量抗英夫利昔单抗的总抗体及其在炎症性肠病患者中的临床相关性。

Development of a C1q-immobilized (Cim) assay to measure total antibodies to infliximab and its clinical relevance in patients with inflammatory bowel disease.

机构信息

Department of Internal Medicine, Division of IBD, Tokyo Yamate Medical Centre, Tokyo, Japan.

Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan.

出版信息

Cytokine. 2019 Aug;120:54-61. doi: 10.1016/j.cyto.2019.02.014. Epub 2019 Apr 16.

DOI:10.1016/j.cyto.2019.02.014

PMID:31003189

Abstract

OBJECTIVE

Determination of antibodies to infliximab (ATI) is desirable for the management of patients with inflammatory bowel disease (IBD) who receive infliximab. Conventional ligand-binding ATI-assays detect only free-form of ATI, potentially increasing the proportion of patients with undetectable ATI, but with adequate trough infliximab (TRI) level who experience loss of response (LOR) to infliximab. We investigated this assertion using a novel ATI-Cim assay.

METHODS

An ATI-Cim assay was developed by utilizing a C1q-immobilized plate, detecting free-form and ATI-infliximab complexes. Plasma ATI in 137 consecutive IBD patients, 56 with sustained clinical response (SCR), 76 with LOR and 5 with infusion reactions was measured.

RESULTS

ATI levels reached a plateau following addition of up to 25 μg/mL infliximab to different concentrations of free-form ATI. ATI concentration did not significantly change during infliximab infusion (P = 0.4316). ATI concentration > 0.153 μg/mL was associated with LOR (odds ratio 3.0: 95%, confidence interval 1.5 to 6.1, P = 0.0029). The number of patients with undetectable ATI was higher in SCR than in LOR, 53.6% vs 22.4% (P = 0.0004). Patients with SCR and LOR were divided into 4 subgroups by combined cut-off ATI and TRI values. (A) ATI > 0.153 μg/mL and TRI ≤ 2 μg/mL; (B) ATI > 0.153 μg/mL and TRI > 2 μg/mL; (C) ATI ≤ 0.153 μg/mL and TRI ≤ 2 μg/mL; (D) ATI ≤ 0.153 μg/mL and TRI > 2 μg/mL. The frequency of LOR showed a decreasing trend from subgroup A to D, 80.8%, 64.1%, 55.2% and 36.8%, respectively (P = 0.0003).

CONCLUSIONS

The measured ATI level appeared to define the patients' response to infliximab. Combining ATI and trough infliximab levels should help to understand the mechanism of LOR and make therapeutic algorithms.

摘要

目的

为了管理接受英夫利昔单抗（IFX）治疗的炎症性肠病（IBD）患者，确定针对 IFX 的抗体（ATI）是可取的。传统的配体结合 ATI 检测仅检测游离形式的 ATI，这可能会增加检测不到 ATI 的患者比例，但具有足够的 IFX 谷浓度（TRI），这些患者经历英夫利昔单抗失效（LOR）。我们使用新型 ATI-Cim 检测来研究这一说法。

方法

通过利用 C1q 固定化板，检测游离形式和 ATI-英夫利昔单抗复合物，开发了 ATI-Cim 检测。测量了 137 例连续 IBD 患者的血浆 ATI，其中 56 例持续临床缓解（SCR），76 例发生 LOR，5 例发生输注反应。

结果

当向不同浓度的游离 ATI 中加入高达 25μg/mL 的英夫利昔单抗时，ATI 水平达到了一个平台。在英夫利昔单抗输注期间，ATI 浓度没有显著变化（P=0.4316）。ATI 浓度>0.153μg/mL 与 LOR 相关（比值比 3.0：95%置信区间 1.5 至 6.1，P=0.0029）。在 SCR 中检测不到 ATI 的患者比例高于 LOR，分别为 53.6%和 22.4%（P=0.0004）。根据联合 ATI 和 TRI 值的截点，将 SCR 和 LOR 患者分为 4 个亚组。（A）ATI>0.153μg/mL 和 TRI≤2μg/mL；（B）ATI>0.153μg/mL 和 TRI>2μg/mL；（C）ATI≤0.153μg/mL 和 TRI≤2μg/mL；（D）ATI≤0.153μg/mL 和 TRI>2μg/mL。从亚组 A 到 D，LOR 的频率呈下降趋势，分别为 80.8%、64.1%、55.2%和 36.8%（P=0.0003）。