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Model‐Informed Drug Development of the Masked Anti‑PD‑L1 Antibody CX‐072
Author(s) -
Stroh Mark,
Green Michelle,
Millard Bjorn L.,
Apgar Joshua F.,
Burke John M.,
Garner Will,
Lu Hong,
Lyman Susan K.,
Desnoyers Luc R.,
Richardson Jennifer,
Hannah Alison,
Kavanaugh W. Michael
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1985
Subject(s) - pharmacokinetics , biodistribution , pharmacology , medicine , population , volume of distribution , drug , oncology , chemistry , biochemistry , in vitro , environmental health
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.