CX-072 is an anti-PD-L1 (programmed death ligand 1) Probody therapeutic (Pb-Tx) designed to be preferentially activated by proteases in the tumor microenvironment and not in healthy tissue. Here, we report the model-informed drug development of CX-072. A quantitative systems pharmacology (QSP) model that captured known mechanisms of Pb-Tx activation, biodistribution, elimination, and target engagement was used to inform clinical translation. The QSP model predicted that a trough level of masked CX-072 (intact CX-072) of 13-99 nM would correspond to a targeted, 95% receptor occupancy in the tumor. The QSP model predictions appeared consistent with preliminary human single-dose pharmacokinetic (PK) data following CX-072 0.03-30.0 mg/kg as monotherapy: CX-072 circulated predominantly as intact CX-072 with minimal evidence of target-mediated drug disposition. A preliminary population PK (POPPK) analysis based upon 130 subjects receiving 0.03-30.0 mg/kg as monotherapy included a provision for a putative time-dependent and dose-dependent antidrug antibody (ADA) effect on clearance (CL) with a mixture model. Preliminary POPPK estimates for intact CX-072 time-invariant CL and volume of distribution were 0.306 L/day and 4.84 L, respectively. Exposure-response analyses did not identify statistically significant relationships with best change from baseline sum of measurements and either adverse events of grade ≥ 3 or of special interest. Simulations suggested that > 95% of patients receiving CX-072 10 mg/kg every two weeks would exceed the targeted trough level regardless of ADA, and that dose adjustment by body weight was not necessary, supporting a fixed 800 mg dose for evaluation in phase II.