Quantitative Systems Pharmacology Model of a Masked, Tumor‐Activated Antibody

PROBODY therapeutics (Pb‐Tx) are protease‐activatable prodrugs of monoclonal antibodies (mAbs) designed to target tumors where protease activity is elevated while avoiding normal tissue. They are composed of a parental mAb, a mask that inhibits antibody binding to target, and a protease‐cleavable substrate between the mask and the mAb. We report a quantitative systems pharmacology model for the rational design and clinical translation of Pb‐Tx. The model adequately described monkey pharmacokinetic data following the administration of six anti‐CD166 Pb‐Tx of varying mask strength and substrate cleavability and captured the trend of decreasing Pb‐Tx systemic clearance with increasing mask strength. Projections to humans suggested both higher levels of Pb‐Tx in tumor relative to parental mAb and an optimal mask strength for maximizing tumor receptor–mediated uptake. Simulations further suggested the majority of circulating species in humans would be intact/masked Pb‐Tx, with no significant flux of cleaved/activated species from tumor to the systemic compartment.