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-1ß 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.
