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.

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）靶向靶向肿瘤坏死因子α（TNF-A）的药物，例如Remicade（英夫利昔单抗），是重磅炸弹毒品 - 英夫利昔单抗的全球销量在2016年接近6B美元。但是，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疗法没有反应归纳，而其他人会随着时间的流逝而失去反应。给药效率低下的主要原因包括刚性剂量在治疗患者中的时间表和抗药物抗体（ADA）反应的经常发展。临床数据强烈指出需要对MAB药物进行治疗剂量监测以确保最佳治疗每个患者的窗户。虽然有基于实验室的测试方法可用，但没有用于保健的测试测量英夫利昔单抗或ADA的浓度。该项目的目的是发展横向流动用于快速测量手指粘液样品中游离英夫利昔单抗和ADA水平的免疫测定（LFA）。我们的专有技术将抗原的小胡椒模拟物（Veritopes™）作为特定的捕获试剂。我们的测试基于配体结合活性，因此有望检测父型MAB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）。我们以前有资格获得技术可行性基于Veritope的LFA，用于检测患者血清中利妥昔单抗浓度。这个项目的目标是：1）生成针对英夫利昔单抗的Veritope，并在LFA中实施肽以进行测量在护理点上血液中的自由英夫利昔单抗水平，2）使用a的艾尔夫里昔单抗检测ADA 补充含有初始酸解离步骤的护理点LFA，3）验证免费药物和使用患者样品ADA LFA。这些创新的产品将满足未满足的临床需求，以快速，成本有效且准确的剂量监测测定法。通过数据驱动的个性化方案进行精确剂量改善治疗结果并最大程度地利用英夫利昔单抗。