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 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.