Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors
Fig 8
Local and global sensitivity of model output to association and dissociation rate constants and the initial antibody and receptor concentrations.
A, Local sensitivity analysis of model output with varying rate constants and initial concentrations. 10 nM baseline BS1 concentration, [IL-6R] = [IL-8R] = 5 × 104 receptors/cell, and output at t = 2 hours for all simulations. Area Under the Curve (AUC) is calculated as the integration of the BS1-receptor complex concentration over time, determined for the ternary complexes and for the total bound receptor (IL-6R + IL-8R). Sensitivity is calculated as the percentage change in the output divided by the percentage change in the parameter (10% for these simulations). B, Global sensitivity of fractional bound receptor concentration over varying rate constant value. Each parameter was varied over two orders of magnitude below and above its optimized value. Fractional occupancy is determined as the fraction of total receptor (IL-6R + IL-8R) that is bound to BS1 in a particular complex type, separated for ternary complexes and total bound in binary or ternary complexes. Simulations were performed for 24 hours after antibody dosing, and [IL-6R] = [IL-8R] = 5 × 104 receptors/cell for all simulations.