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

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.The goal of this project is to develop a computational modeling software product to better identify liver injury liabilities (biologic-induced liver injury; “BILI”) in new biologic drug candidates using data from mechanistic experiments in a human liver biomimetic as inputs to predict BILI in humans. The prototype software will represent important aspects of liver function/dysfunction in humans with emphasis on large molecule (biologics) effects. The project will provide a prototype system that can be used to inform preclinical biologic development, inform clinical trial designs, predict product safety, evaluate potential adverse event mechanisms, as well as contribute to the understanding of mechanisms involved in biologic-induced liver injury.