A minimal physiologically based pharmacokinetic model to study the combined effect of antibody size, charge, and binding affinity to FcRn/antigen on antibody pharmacokinetics.

Protein therapeutics have revolutionized the treatment of a wide range of diseases. While they have distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, the relationship between the physicochemical properties and PK is still largely unknown. In this work we present a minimal physiologically-based pharmacokinetic (mPBPK) model that incorporates a multivariate quantitative relation between a therapeutic's physicochemical parameters and its corresponding ADME properties. The model's compound-specific input includes molecular weight, molecular size (Stoke's radius), molecular charge, binding affinity to FcRn, and specific antigen affinity. Through derived and fitted empirical relationships, the model demonstrates the effect of these compound-specific properties on antibody disposition in both plasma and peripheral tissues using observed PK data in mice and humans. The mPBPK model applies the two-pore hypothesis to predict size-based clearance and exposure of full-length antibodies (150 kDa) and antibody fragments (50-100 kDa) within a onefold error. We quantitatively relate antibody charge and PK parameters like uptake rate, non-specific binding affinity, and volume of distribution to capture the relatively faster clearance of positively charged mAb as compared to negatively charged mAb. The model predicts the terminal plasma clearance of slightly positively and negatively charged antibody in humans within a onefold error. The mPBPK model presented in this work can be used to predict the target-mediated disposition of a drug when compound-specific and target-specific properties are known. To our knowledge, a combined effect of antibody weight, size, charge, FcRn, and antigen has not been incorporated and studied in a single mPBPK model previously. By conclusively incorporating and relating a multitude of protein's physicochemical properties to observed PK, our mPBPK model aims to contribute as a platform approach in the early stages of drug development where many of these properties can be optimized to improve a molecule's PK and ultimately its efficacy.

Cross-Domain Text Mining of Pathophysiological Processes Associated with Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. This study's goal was to identify the signaling drivers and pathways that modulate glomerular endothelial dysfunction in DKD via artificial intelligence-enabled literature-based discovery. Cross-domain text mining of 33+ million PubMed articles was performed with SemNet 2.0 to identify and rank multi-scalar and multi-factorial pathophysiological concepts related to DKD. A set of identified relevant genes and proteins that regulate different pathological events associated with DKD were analyzed and ranked using normalized mean HeteSim scores. High-ranking genes and proteins intersected three domains-DKD, the immune response, and glomerular endothelial cells. The top 10% of ranked concepts were mapped to the following biological functions: angiogenesis, apoptotic processes, cell adhesion, chemotaxis, growth factor signaling, vascular permeability, the nitric oxide response, oxidative stress, the cytokine response, macrophage signaling, NFκB factor activity, the TLR pathway, glucose metabolism, the inflammatory response, the ERK/MAPK signaling response, the JAK/STAT pathway, the T-cell-mediated response, the WNT/ß-catenin pathway, the renin-angiotensin system, and NADPH oxidase activity. High-ranking genes and proteins were used to generate a protein-protein interaction network. The study results prioritized interactions or molecules involved in dysregulated signaling in DKD, which can be further assessed through biochemical network models or experiments.

Logic-Based Modeling of Inflammatory Macrophage Crosstalk with Glomerular Endothelial Cells in Diabetic Kidney Disease.

Diabetic kidney disease is a complication in 1 out of 3 patients with diabetes. Aberrant glucose metabolism in diabetes leads to an immune response causing inflammation and to structural and functional damage in the glomerular cells of the kidney. Complex cellular signaling lies at the core of metabolic and functional derangement. Unfortunately, the mechanism underlying the role of inflammation in glomerular endothelial cell dysfunction during diabetic kidney disease is not fully understood. Computational models in systems biology allow the integration of experimental evidence and cellular signaling networks to understand mechanisms involved in disease progression. We built a logic-based ordinary differential equations model to study macrophage-dependent inflammation in glomerular endothelial cells during diabetic kidney disease progression. We studied the crosstalk between macrophages and glomerular endothelial cells in the kidney using a protein signaling network stimulated with glucose and lipopolysaccharide. The network and model were built using the open-source software package Netflux. This modeling approach overcomes the complexity of studying network models and the need for extensive mechanistic details. The model simulations were fitted and validated against available biochemical data from in vitro experiments. The model identified mechanisms responsible for dysregulated signaling in macrophages and glomerular endothelial cells during diabetic kidney disease. In addition, we investigated the influence of signaling interactions and species that on glomerular endothelial cell morphology through selective knockdown and downregulation. We found that partial knockdown of VEGF receptor 1, PLC-γ, adherens junction proteins, and calcium partially recovered the endothelial cell fenestration size. Our model findings contribute to understanding signaling and molecular perturbations that affect the glomerular endothelial cells in the early stage of diabetic kidney disease.