Personalized precision dosing of anti-TNF biologic therapies

抗 TNF 生物疗法的个性化精确剂量

基本信息

批准号：
9888300
负责人：
BRADLEY T MESSMER
金额：
$ 84.11万
依托单位：
ABREOS BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888300
关键词：
Acids Acute Antibodies Antibody Response Antibody-drug conjugates Antigens Autoimmune Diseases Autoimmune Process Bedside Testings Biological Biological Assay Biological Response Modifier Therapy Biological Sciences Blood Blood drug level result Blood specimen Body Surface Area Body Weight Cells Clinical Clinical Data Clinical Research Collaborations Complement Conjugating Agent Crohn&apos s disease Data Detection Development Device or Instrument Development Devices Disease Dissociation Dose Drops Drug Kinetics Drug Targeting Enrollment Ensure Enzyme-Linked Immunosorbent Assay Fab Immunoglobulins Failure Fingers Future Goals Gold Colloid Health Immune response Immune system Immunoassay Individual Inflammatory Label Laboratories Lateral Lead Ligand Binding Link Malignant Neoplasms Measurement Measures Membrane Methods Monitor Monoclonal Antibodies Monoclonal Antibody Therapy Observational Study Parents Patients Peptides Performance Pharmaceutical Preparations Phase Physiological Population Production Protocols documentation Quality Control Reagent Regimen Reporting Sales Sampling Schedule Sensitivity and Specificity Serum Specificity Structure TNF gene Technology Testing Therapeutic Therapeutic Monoclonal Antibodies Time Treatment outcome Ulcerative Colitis Universities Validation Work antigen binding base clinically relevant cost effective dosage drug efficacy expectation experience improved infliximab innovation meetings novel peptidomimetics performance tests point of care portability primary endpoint recruit response rituximab side effect treatment choice

项目摘要

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.

单克隆抗体越来越多地用于治疗自身免疫性疾病和炎症性疾病。靶向肿瘤坏死因子 α (TNF-a) 的单克隆抗体药物，例如 Remicade（英夫利昔单抗），是重磅炸弹药品——2016 年英夫利昔单抗的全球销售额接近 6B 美元。然而，批准后研究表明使用这些抗 TNF-a 生物制剂的效率低下；一些患者对 mAb 疗法没有反应；诱导，而其他人随着时间的推移失去反应，剂量低效的主要原因包括严格的剂量。时间表和治疗患者抗药物抗体（ADA）反应的频繁发生。数据强烈表明需要对单克隆抗体药物的治疗剂量进行监测，以确保最佳治疗效果虽然可以使用基于实验室的测试方法，但没有针对每个患者的即时测试。测量英夫利昔单抗或 ADA 的浓度该项目的目标是开发浓度侧流。免疫分析 (LFA)，用于快速测量指尖采血样本中游离英夫利昔单抗和 ADA 的水平。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。我们的测试基于配体结合活性，因此有望检测母体单克隆抗体药物（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-abda）。基于 Veritope 的 LFA 用于检测患者血清中的利妥昔单抗浓度该项目的目标。的目的是：1) 生成英夫利昔单抗特异性的 Veritope 并在 LFA 中实施该肽以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即时 LFA，以及 3) 验证游离药物和使用患者样本的 ADA LFA 将满足未满足的快速、低成本的临床需求。通过数据驱动的个性化方案进行有效、准确的剂量监测测定。改善治疗结果并最大限度地有效利用英夫利昔单抗。