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

Clin Transl Sci. 2018 May;11(3):296-304. doi: 10.1111/cts.12535. Epub 2018 Jan 19.


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.

MeSH terms

  • Animals
  • Antibodies, Bispecific / pharmacology*
  • Antigens, CD20 / immunology
  • CD3 Complex / antagonists & inhibitors
  • CD3 Complex / immunology
  • Cell Movement / drug effects
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Transgenic
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism


  • Antibodies, Bispecific
  • Antigens, CD20
  • CD3 Complex