Impacts of anti-drug antibodies on pharmacokinetic and pharmacodynamic actions of cell-permeable middle molecule peptide drug

The administration of peptide drugs can induce the generation of anti-drug antibodies (ADAs), potentially leading to unwanted effects such as reduced drug efficacy, which is often seen with therapeutic monoclonal antibodies. However, the influence of ADAs on the pharmacokinetic and pharmacodynamic properties of cell-permeable middle molecules remains unclear. This study investigated ADA impacts using AP2151, a middle molecule cyclic peptide with high cell membrane permeability. ADAs were generated by immunizing rabbits with an AP2151 analog conjugated to keyhole limpet hemocyanin. A dialysis experiment was then performed to determine the binding affinity between AP2151 and the purified ADAs. Using in-house experimental data, we established a SimBiology model to simulate the pharmacokinetic profiles of AP2151 in varying ADA concentrations. The simulation results suggested that higher ADA levels (up to several micromolar) would more strongly increase the total plasma concentrations of AP2151 without apparently changing the free concentrations. Thus, according to the free drug theory, the pharmacological effect was predicted to remain constant despite the presence of ADAs. These predictions were subsequently confirmed by an in vivo study, in which mice were administered with AP2151 following a preliminary infusion with or without ADAs. Our findings suggest that in the case of cell-permeable middle molecules, ADAs raise total drug concentrations but have little impact on the drug efficacy. SIGNIFICANCE STATEMENT: We conducted both model-based simulation and in vivo experiments to examine anti-drug antibody impacts on a cell-permeable middle molecule drug. As predicted by the model and confirmed by mouse studies, the presence of anti-drug antibodies increases the total plasma concentration of the drug without compromising its pharmacological effects, highlighting the significance of model analysis and may contribute to the understanding of middle molecule compounds.