Personalized precision dosing of anti-TNF biologic therapies

生物制剂越来越多地被用于治疗自身免疫性和炎症性疾病。单抗 (单抗)靶向肿瘤坏死因子-a的药物，如Remicade(英夫利昔单抗)，是重磅炸弹 药物-2016年英夫利昔单抗的全球销售额接近60亿美元。然而，审批后的研究表明， 这些抗肿瘤坏死因子-a生物制剂的使用效率低下；一些患者对单抗治疗没有反应 感应，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严格的给药 在接受治疗的患者中，抗药物抗体(ADA)反应的时间表和频繁发生。临床部 数据有力地表明，需要对单抗药物进行治疗剂量监测，以确保最佳治疗 打开每个病人的窗户。虽然基于实验室的测试方法是可用的，但没有针对以下方面的护理点测试 测量英夫利昔单抗或ADAs的浓度。该项目的目标是发展侧向流动。 用于快速测定手指棒血样本中游离英夫利昔单抗和ADA水平的免疫分析(LFA)。 我们的专利技术使用抗原的小肽模拟物(Veritope™)作为特定的捕获试剂。 我们的测试是基于配体结合活性，因此有望检测到亲本单抗药物(英夫利昔单抗)， 以及新的生物仿制药(英夫利昔单抗-dyyb、英夫利昔单抗-阿博达)。我们先前鉴定了技术可行性 基于Veritope的LFA检测患者血清中利妥昔单抗浓度。这个项目的目标是 目的是：1)生成英夫利昔单抗的特异性Veritope，并在LFA中实现该肽用于测量 护理点血液中的游离英夫利昔单抗水平，2)使用 补充包含初始酸解离步骤的护理点LFA，以及3)验证游离药物和 Ada LFA使用患者样本。这些创新的产品将以快速、成本的方式满足未得到满足的临床需求 有效、准确的剂量监测分析。通过数据驱动的个性化方案进行精确给药将 改善治疗结果，最大限度地有效使用英夫利昔单抗。

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.