Enzyme - Switch sensors for therapeutic drug monitoring of immunotherapies.
Enzyme - Switch sensors for therapeutic drug monitoring of immunotherapies.
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DOI：
10.1016/j.bios.2023.115488
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发表时间：
2023-10-01
影响因子：
12.6
通讯作者：
中科院分区：
文献类型：
--
作者：
治疗性单克隆抗体（TmAb）已成为许多癌症和自身免疫性疾病的有效治疗方法。然而，TmAb治疗的药代动力学的患者间差异较大，需要密切的治疗药物监测（TDM），以优化个体患者的剂量。在这里，我们展示了一种方法，用于实现快速，灵敏的定量两种单克隆抗体治疗使用先前描述的酶开关传感器平台。酶开关传感器由β-内酰胺酶- β-内酰胺酶抑制剂蛋白（BLA-BLIP）复合物和两个抗独特型结合蛋白（Affimer蛋白）作为识别元件组成。BLA-BLIP传感器被工程化以通过开发将新的合成结合试剂掺入到这些mAb中的每一种的构建体来检测两种TmAb（曲妥珠单抗和伊匹单抗）。曲妥珠单抗和伊匹单抗在高达1%的血清中以低于nM的灵敏度成功监测，因此涵盖了相关的治疗范围。尽管采用了模块化设计，但BLA-BLIP传感器在检测另外两种TmAb（利妥昔单抗和阿达木单抗）时未成功，对此进行了解释。总之，BLA-BLIP传感器为曲妥珠单抗和伊匹单抗的TDM提供了一种快速生物传感器，具有改善治疗的潜力。该平台的灵敏度及其快速作用将适用于床旁监护（床旁监护）。
Therapeutic monoclonal antibodies (TmAb) have emerged as effective treatments for a number of cancers and autoimmune diseases. However, large interpatient disparities in the pharmacokinetics of TmAb treatment requires close therapeutic drug monitoring (TDM) to optimise dosage for individual patients. Here we demonstrate an approach for achieving rapid, sensitive quantification of two monoclonal antibody therapies using a previously described enzyme switch sensor platform. The enzyme switch sensor consists of a β-lactamase – β-lactamase inhibitor protein (BLA-BLIP) complex with two anti-idiotype binding proteins (Affimer proteins) as recognition elements. The BLA-BLIP sensor was engineered to detect two TmAbs (trastuzumab and ipilimumab) by developing constructs incorporating novel synthetic binding reagents to each of these mAbs. Trastuzumab and ipilimumab were successfully monitored with sub nM sensitivity in up to 1% serum, thus covering the relevant therapeutic range. Despite the modular design, the BLA-BLIP sensor was unsuccessful in detecting two further TmAbs (rituximab and adalimumab), an explanation for which was explored. In conclusion, the BLA-BLIP sensors provide a rapid biosensor for TDM of trastuzumab and ipilimumab with the potential to improve therapy. The sensitivity of this platform alongside its rapid action would be suitable for bedside monitoring in a point-of-care (PoC) setting.
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