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-1ß 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.
Public Health Relevance Statement: 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.
Project Terms: Acute Disease; acute disease/disorder; acute disorder; Albumins; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Antibodies; Bile fluid; Bile; Bile Juice; Bile Acids; Bioenergetics; Biological Assay; Assay; Bioassay; Biologic Assays; Blood Vessels; vascular; Cells; Cell Body; Chronic Disease; Chronic Illness; chronic disorder; Clinical Trials; Database Management Systems; Data Base Management; Data Base Management Systems; database management; database systems; relational database management systems; Cessation of life; Death; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Fibrosis; Fluorescence; Goals; Health; Blood Tests; Hematologic Tests; Hematological Tests; Hematology Testing; Homeostasis; Autoregulation; Physiological Homeostasis; Human; Modern Man; In Vitro; Inflammation; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; Liver; hepatic body system; hepatic organ system; liver transplantation; Hepatic Transplantation; Liver Grafting; Liver Transplant; Necrosis; Necrotic; Patients; Program Development; Publishing; Fc Receptor; antibody receptor; Recommendation; Natural regeneration; Regeneration; regenerate; Research; Safety; Computer software; Software; Software Tools; Computer Software Tools; Mass Spectrum Analysis; Mass Photometry/Spectrum Analysis; Mass Spectrometry; Mass Spectroscopy; Mass Spectrum; Mass Spectrum Analyses; Educational process of instructing; Teaching; Testing; Interleukin 6 Receptor; CD126 Antigens; CD126 Receptor; IL-6 Receptors; IL6 Receptors; Measures; Terfenadine; Terfenidine; Taurine Cholate; Taurocholate; Glial Growth Factor; GGF Protein; Injury; injuries; base; Hepatic; Clinical; Phase; Biological; Medical; Series; Ensure; Endothelial Cells; hepatic acinus structure; Liver Acinus; Hepatocyte; Hepatic Cells; Hepatic Parenchymal Cell; Liver Cells; Perisinusoidal Space; Space of Disse; liver function; Oxidative Stress; Functional disorder; Dysfunction; Physiopathology; pathophysiology; fexofenadine; Immunological response; host response; immune system response; immunoresponse; Immune response; Exposure to; Attenuated; tool; Immunes; Immune; Source; System; Equation; human data; Isoforms; Protein Isoforms; success; biological sensor; Biosensor; bile acid transporter; Biologic Development; simulation; novel technologies; new technology; NRG Proteins; Neu-Differentiation Factor; Sensory-and-motor-derived factor; Neuregulins; response; case control; drug development; Biological Mimetics; Biomimetics; Adverse Experience; Adverse event; Molecular Interaction; Binding; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; Institution; small molecule; Address; Biological Testing; Data; Preclinical Models; Pre-Clinical Model; Clinical Data; Clinical Trials Design; Validation; Development; developmental; pre-clinical; preclinical; design; designing; Outcome; clinical effect; prototype; commercialization; drug candidate; liver injury; Injury to Liver; hepatic damage; hepatic injury; liver damage; Differential Equation; Differential Algebraic Equation; clinical biomarkers; clinically useful biomarkers; Growth Factor; Growth Agents; Growth Substances; Proteins Growth Factors; experimental study; experiment; experimental research; Adaptive Immune System; acquired immune system; Immune checkpoint inhibitor; Checkpoint inhibitor; immune check point inhibitor; microphysiology system; microphysiologic model; microphysiologic platform; microphysiologic system; microphysiology model; microphysiology platform; Computer Models; Computerized Models; computational modeling; computational models; computer based models; computerized modeling; tocilizumab; Actemra
