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

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.

Mitigating the risk of cytokine release syndrome in a Phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling

“…We also used a simplified representation of pharmacokinetics (a linear two-compartment model) for prospective simulation in human. We acknowledge that the preclinical PK is nonlinear as demonstrated by the population PK model in 44 , however, in the absence of clinical PK data, the linear PK model was used for the purpose of IL6 predictions, as cytokine levels typically peak and drop within 24-48 h, for which the projected PK profiles from the linear and nonlinear PK models are comparable. Future work can include the PK data from clinical studies.…”

Target‐Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy

“…In the future, the model and its approximation can be extended with (i) TC effects on target cells, (ii) T cell rebound phenomena, and (iii) integration of local geometrical structures on the cell surface for the cross‐linking binding reactions . Inclusion of geometrical structures leads to mathematical models of the form Eqs.…”

“…In the future, the model and its approximation can be extended with (i) TC effects on target cells, 28 (ii) T cell rebound phenomena, 31 and (iii) integration of local geometrical…”

Quantitative Clinical Pharmacology of T‐Cell Engaging Bispecifics: Current Perspectives and Opportunities

“…Cyno PK could be scaled to project human PK through allometric scaling for clearance and volume parameters . 15 In scenarios where the TDB may be subject to target-mediated drug disposition (TMDD) (see section PK Considerations), human PK predictions should account for differences in target expression, binding affinity, and/or other intrinsic differences between cyno and human. Notably, anti-drug antibodies (ADAs) which oftentimes emerge in cynos may not directly translate to humans.…”

“…For example, PopPK of mosunetuzumab and REGN1979 have been characterized preclinically and/or clinically with a time-varying clearance, consistent with traditional anti-CD20 antibodies (e.g., rituximab and obinutuzumab), to represent target (B-cell) binding and associated target modulation with treatment. 15,24 Higher TDB clearance may be anticipated for agents with higher CD3 affinity, as illustrated with the CLL-1/CD3 bispecific antibody. 25 In general, PK covariate investigations should consider impacts of disease status (e.g., tumor burden, cachexia)…”