Personalized precision dosing of anti-TNF biologic therapies

生物制剂越来越多地用于治疗自身免疫性和炎症性疾病。单克隆抗体 (mAb)靶向肿瘤坏死因子-α（TNF-α）的药物，如Remicade（英夫利西单抗）， 2016年英夫利西单抗的全球销售额接近60亿美元。然而，批准后的研究表明， 这些抗TNF-α生物制剂的使用效率低下;一些患者在接受治疗后对mAb治疗没有反应。 诱导，而另一些则随着时间的推移而失去反应。给药效率低下的主要原因包括刚性给药 时间表和治疗患者中频繁出现抗药抗体（ADA）应答。临床 数据有力地表明需要监测mAb药物的治疗剂量， 每个病人的窗口虽然基于实验室的测试方法是可用的，但没有即时测试， 测量英夫利西单抗或ADA的浓度。本项目的目标是开发侧流 免疫分析（LFA）用于快速测量手指针刺血样中游离英夫利西单抗和ADA水平。 我们的专有技术使用抗原的小肽模拟物（Veritopes™）作为特异性捕获试剂。 我们的检测基于配体结合活性，因此预期可检测母体mAb药物（英夫利西单抗）， 以及新的生物类似药（英夫利昔单抗-dyyb、英夫利昔单抗-abda）。我们之前对技术可行性进行了鉴定， 用于检测患者血清中利妥昔单抗浓度的基于Veritope的LFA。本项目的目标 1）产生英夫利西单抗特异性的Veritope，并在LFA中实施肽，用于测量 2）使用ADA检测法证明英夫利西单抗的ADA检测， 补充包含初始酸解离步骤的护理点LFA，以及3）验证游离药物， 使用患者样本的ADA LFA。这些创新的产品将满足未满足的临床需求， 有效和准确的剂量监测分析。通过数据驱动的个性化方案实现精确给药， 改善治疗结果，最大限度地提高英夫利西单抗的有效利用。

Biologics are increasingly used in the treatment of autoimmune and inflammatory diseases. Monoclonal antibody (mAb) drugs that target tumor necrosis factor alpha (TNF-a), such as Remicade (infliximab), are blockbuster drugs—global sales of infliximab were close to $6B in 2016. However, post-approval studies have revealed inefficiencies in the use of these anti-TNF-a biologics; some patients do not respond to mAb therapies upon induction, whereas others lose response over time. Primary causes of dosing inefficiency include a rigid dosing schedule and the frequent development of anti-drug antibody (ADA) responses in treated patients. The clinical data strongly point to the need for therapeutic dose monitoring of mAb drugs to ensure an optimal therapeutic window in every patient. While laboratory-based test methods are available, there are no point-of-care tests for measuring the concentration of either infliximab or ADAs. The goal of this project is to develop lateral flow immunoassays (LFAs) for rapid measurement of free infliximab and ADA levels in finger-stick blood samples. Our proprietary technology uses small peptide mimetics (Veritopes™) of the antigen as a specific capture reagent. Our tests are based on ligand-binding activity, and are thus expected to detect the parent mAb drug (infliximab), as well as new biosimilars (infliximab-dyyb, infliximab-abda). We previously qualified the technical feasibility of Veritope-based LFAs for the detection of rituximab concentration in patient serum. The objectives of this project are to: 1) generate Veritope specific for infliximab and implement the peptide in a LFA for the measurement of free infliximab levels in blood at the point-of-care, 2) Demonstrate ADA detection for infliximab using a complement point-of-care LFA that incorporates an initial acid dissociation step, and 3) validate free drug and ADA LFA using patient samples. These innovative products will fulfill of an unmet clinical need for a rapid, cost effective, and accurate dose monitoring assay. Precision dosing through data-driven, personalized regimens will improve treatment outcomes and maximize the efficient use of infliximab.