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: 10580097
• 负责人: Kyunghee Yang
• 金额: $ 83.44万
• 依托单位: SIMULATIONS PLUS, 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580097
• 关键词: Acute Disease; Address; Adverse event; Anti-Inflammatory Agents; Award; Biologic Development; Biological; Biological Models; Biological Products; Biological Testing; Biomimetics; Biosensor; Blood Tests; Cells; Chronic Disease; Clinical; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Computer Models; Computer software; Data; Database Management Systems; Development; Disease; Drug Interactions; Educational process of instructing; Fc Receptor; Fibrosis; Functional disorder; Glial Growth Factor; Goals; Growth Factor; Hepatic; Hepatocyte; Human; Immune checkpoint inhibitor; Individual; Inflammation; Institution; Interleukin 6 Receptor; Liver; Liver diseases; Marketing; Measurement; Mediating; Medical; Modeling; Necrosis; Neuregulins; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Population; Pre-Clinical Model; Program Development; Protein Isoforms; Proteins; Publishing; Recommendation; Research; Safety; Source; Stress; T cell response; T-Lymphocyte; Testing; Toxicology; Vascularization; adaptive immune response; base; commercialization; comorbidity; design; drug candidate; drug development; drug induced liver injury; efficacy evaluation; end stage disease; experimental study; hepatic acinus structure; human data; human disease; improved; inter-individual variation; liver function; liver injury; liver transplantation; microphysiology system; new technology; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; pre-clinical; prototype; response; simple steatosis; simulation; small molecule; tocilizumab; tool; transcriptome; treatment duration

The goal of this project is to develop novel technologies for predicting biologics-induced liver injury caused by anti-inflammatory biologics such as anti-IL6 receptor antibody (e.g., tocilizumab), growth factors such as neuregulin-1β isoform, glial growth factor 2 (GGF2), other biologics (e.g., checkpoint inhibitors), as well as combination therapies involving biologics. 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 further develop the prototype BIOLOGXsym, a computational modeling software, from the Phase 1 award into a product for use in testing biologics (preclinical, clinical, or after-market) and combination therapies including biologics (e.g., in combination with a small molecule) for potential to cause biologics-induced liver injury. As part of developing these new technologies, 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 from healthy individuals as well as diseased individuals with the aim of using vLAMPS as the eventual key source of input data for BIOLOGXsym simulations. To validate the product, we will perform simulations using BIOLOGXsym for various biologics monotherapies and combination therapies in simulated populations (SimPops) of healthy individuals and diseased individuals, and then compare the simulation results to published clinical trial data. Once validated, the product will be commercialized for use by our existing base of pharmaceutical company customers, regulatory agencies, academic institutions for teaching and academic research use, and new users.

该项目的目标是开发预测生物诱导肝损伤的新技术 由抗IL 6受体抗体等抗炎生物制剂引起的损伤（例如， 托珠单抗）、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）、其他 生物制剂（例如，检查点抑制剂），以及涉及生物制剂的联合疗法。 生物制剂现在占开发中药物的一半以上，并且有潜力 解决许多急性疾病、慢性疾病和其他未满足的医疗需求。生物制品- 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。在一些 例生物制剂性肝损伤患者需行肝移植。一 一个重要的问题是，虽然生物制剂的开发和使用有所增加，但缺乏 可用于评估生物制品引起生物制品诱导肝脏的能力的工具 损伤例如，由于生物制剂通常是专门针对人类目标设计的， 用于小分子药物开发的标准临床前模型不足以 评估生物制品的有效性或安全性。在这个项目中，我们将进一步开发原型 BIOLOGXsym，一个计算建模软件，从第一阶段的奖项变成一个产品， 用于测试生物制剂（临床前、临床或售后）和联合治疗，包括 生物制剂（例如，与小分子组合）形成引起生物诱导的 肝损伤作为开发这些新技术的一部分，我们还将进一步发展国家- 最先进的人肝MPS（vLAMPS），用于评估来自人肝的生物制剂的肝脏效应 来自健康个体和患病个体的细胞，目的是使用vLAMPS作为 BIOLOGXsym模拟输入数据的最终关键来源。为了验证产品，我们 将使用BIOLOGXsym对各种生物制剂单一疗法进行模拟， 在健康个体和患病个体的模拟群体（SimPops）中的组合疗法 个体，然后将模拟结果与已发表的临床试验数据进行比较。一旦 经过验证，该产品将被商业化，供我们现有的制药基地使用。 公司客户、监管机构、教学学术机构 研究用途和新用户。