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

该项目的目标是开发预测生物制剂诱导的肝脏的新技术。 诸如由诸如抗IL6受体抗体的抗炎生物制剂引起的损伤(例如， Tocilizumab)，以及神经调节蛋白-1β亚型、胶质生长因子2等生长因子， 以及其他生物制品(例如，检查点抑制剂)。生物制品现在所占的比例超过 一半的药物正在开发中，并有可能治疗许多急性疾病， 慢性病和其他未得到满足的医疗需求。生物制品引起的肝损伤可表现为 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需要使用。一个重要的问题是，虽然有 增加了生物制品的开发和使用，但缺乏可用于评估 生物制品能够引起生物制品引起的肝损伤。例如，因为生物制品 通常是专门为人类目标设计的，标准的临床前模型用于小型 分子药物开发不足以评估生物制品的有效性或安全性。在……里面 在这个项目中，我们将开发新的技术，作为用于测试的原型 生物制品(临床前、临床或上市后)可能导致生物制品引起的肝 受伤。在开发这项新技术的同时，我们还将进一步开发最先进的 人肝MPS(VLAMPS)评价人肝细胞生物制品对小鼠肝脏的影响 肝腺泡，目的是使用vLAMPS作为以下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。一次 经过验证，该系统将作为一个原型，然后可以扩展为商业化 供我们现有的制药公司客户、监管机构和 学术机构用于教学和学术研究。

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.