Software for Predicting Liver Injury from Biologics Drug Candidates Using Data from a Human Liver Microphysiology System

使用人类肝脏微生理学系统的数据预测生物制剂候选药物肝损伤的软件

• 批准号: 10248834
• 负责人: Brett Alyn Howell
• 金额: $ 10.65万
• 依托单位: DILISYM SERVICES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2021-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248834
• 关键词: Acute Disease; Adaptive Immune System; Address; Adverse event; Albumins; Anti-Inflammatory Agents; Antibodies; Attenuated; Bile Acids; Bile fluid; Binding; Bioenergetics; Biologic Development; Biological; Biological Assay; Biological Testing; Biomimetics; Biosensor; Blood Tests; Blood Vessels; Cells; Cessation of life; Chronic Disease; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Computer Models; Computer software; Data; Database Management Systems; Development; Differential Equation; Educational process of instructing; Endothelial Cells; Ensure; Equation; Exposure to; Fc Receptor; Fibrosis; Fluorescence; Functional disorder; Glial Growth Factor; Goals; Growth Factor; Health; Hepatic; Hepatocyte; Homeostasis; Human; Immune; Immune checkpoint inhibitor; Immune response; In Vitro; Inflammation; Injury; Institution; Interleukin 6 Receptor; Interleukin-6; Liver; Mass Spectrum Analysis; Measures; Medical; Natural regeneration; Necrosis; Neuregulins; Outcome; Oxidative Stress; Patients; Perisinusoidal Space; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pre-Clinical Model; Program Development; Protein Isoforms; Publishing; Recommendation; Research; Safety; Series; Software Tools; Source; System; Taurine Cholate; Terfenadine; Testing; Validation; base; bile acid transporter; case control; clinical biomarkers; clinical effect; commercialization; design; drug candidate; drug development; experimental study; fexofenadine; hepatic acinus structure; human data; liver function; liver injury; liver transplantation; microphysiology system; new technology; pre-clinical; prototype; response; simulation; small molecule; success; tocilizumab; tool

The goal of this project is to develop novel technology for predicting biologics-induced liver injury such as caused by anti-inflammatory biologics such as anti-IL6 receptor antibody (e.g., tocilizumab), and by growth factors such as neuregulin-1β isoform, glial growth factor 2 (GGF2), as well as by other biologics (e.g., checkpoint inhibitors). Biologics now account for more than half of the drugs in development, and have the potential to address many acute diseases, chronic diseases, and other unmet medical needs. Biologics-induced liver injury can manifest as focal hepatocyte necrosis, steatosis, and fibrosis. In some cases, liver transplantation is required for patients with biologics-induced liver injury. A significant problem is that while there is increased development and use of biologics, there lacks tools available for the assessment of biologics for the ability to cause biologics-induced liver injury. For example, because biologics are typically designed specifically for human targets, standard preclinical models used for small molecule drug development are inadequate for assessing the efficacy or safety of biologics. In this project, we will develop novel technology that will serve as a prototype for use in testing biologics (preclinical, clinical, or after-market) for potential to cause biologics-induced liver injury. In developing this new technology, we will also further develop the state-of-the-art human liver MPS (vLAMPS) to assess the liver effects of biologics from human liver cells in the liver acinus with the aim of using vLAMPS as the eventual key source of input data for BIOLOGXsym simulations. Additionally, we will perform validation of this new technology. Once validated, this system will serve as a prototype that can then be expanded for commercialization for use by our existing base of pharmaceutical company customers, regulatory agencies, and academic institutions for teaching and academic research use.

本项目的目标是开发新的技术来预测生物诱导的肝脏 例如由抗炎生物制剂如抗IL 6受体抗体（例如， 托珠单抗），以及生长因子如神经调节蛋白-1 β同种型，神经胶质生长因子2（GGF 2）， 以及其它生物制剂（例如，检查点抑制剂）。生物制剂现在占比超过 一半的药物在开发中，并有可能解决许多急性疾病， 慢性病和其他未满足的医疗需求。生物制剂诱导的肝损伤可表现为 局灶性肝细胞坏死、脂肪变性和纤维化。在某些情况下，肝移植是 生物制剂引起的肝损伤患者所需。一个重要的问题是， 生物制剂的开发和使用增加，缺乏可用于评估 生物制剂引起生物制剂诱导的肝损伤的能力。例如，由于生物 通常是专门为人类目标设计的，标准的临床前模型用于小 分子药物开发不足以评估生物制剂的功效或安全性。在 在这个项目中，我们将开发新的技术，作为测试使用的原型。 生物制剂（临床前、临床或售后）可能导致生物制剂诱导性肝损伤 损伤在开发这项新技术的同时，我们还将进一步发展最先进的 人肝MPS（vLAMPS），以评估来自人肝细胞的生物制剂对肝脏的影响， 目的是使用vLAMPS作为输入数据的最终关键来源， BIOLOGXsym模拟。此外，我们将对这项新技术进行验证。一旦 经过验证，该系统将作为一个原型，然后可以扩大商业化 供我们现有的制药公司客户、监管机构和 学术机构供教学和学术研究使用。