A Preclinical Population Pharmacokinetic Model for Anti‐CD20/CD3 T‐Cell‐Dependent Bispecific Antibodies

作者：Gregory Z. Ferl, Arthur E. Reyes, Liping Laura Sun, Melissa Cheu, Amy Oldendorp, Saroja Ramanujan, Eric Gary Stefanich · 发表于：Clinical and Translational Science · 年份：2018 · DOI：10.1111/cts.12535 · 被引用次数：35 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Chronic Lymphocytic Leukemia Research、CAR-T cell therapy research

Abstract CD20 is a cell‐surface receptor expressed by healthy and neoplastic B cells and is a well‐established target for biologics used to treat B‐cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti‐CD20/CD3 T‐cell‐dependent bispecific antibody BTCT4465A were collected in transgenic mouse and nonhuman primate (NHP) studies. Pronounced nonlinearity in drug elimination was observed in the murine studies, and time‐varying, nonlinear PK was observed in NHPs, where three empirical drug elimination terms were identified using a mixed‐effects modeling approach: i) a constant nonsaturable linear clearance term (7 mL/day/kg); ii) a rapidly decaying time‐varying, linear clearance term (t½ = 1.6 h); and iii) a slowly decaying time‐varying, nonlinear clearance term (t½ = 4.8 days). The two time‐varying drug elimination terms approximately track with time scales of B‐cell depletion and T‐cell migration/expansion within the central blood compartment. The mixed‐effects NHP model was scaled to human and prospective clinical simulations were generated.