Development of a minimal physiologically-based pharmacokinetic/pharmacodynamic model to characterize target cell depletion and cytokine release for T cell-redirecting bispecific agents in humans

Abstract

T cell-redirecting bispecific antibodies (bsAbs) are highly potent tumor-killing molecules. Following bsAb mediated engagement with target cells, T cells get activated and kill target cells while inducing cytokine release, which at higher levels may lead to life-threatening cytokine release syndrome (CRS). Clinical evidence suggests that CRS can be mitigated by implementing a stepwise dosing strategy. Here, we developed a mechanism-based minimal physiologically-based pharmacokinetic/pharmacodynamic (mPBPK/PD) model using reported preclinical and clinical data from blinatumomab. The mPBPK/PD model reasonably captured blinatumomab PK and B cell depletion profiles in blood and in various tissue sites of action (i.e., red marrow perivascular niche, spleen, and lymph nodes) in patients with non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Using interleukin 6 (IL-6) as an example, our model quantitatively characterized the mitigation of cytokine release by a blinatumomab 5-15-60 µg/m²/day stepwise dosing regimen comparing to a 60 µg/m²/day flat dose in NHL patients. Furthermore, by only modifying the system parameters specific for ALL patients, the mPBPK/PD model successfully predicted the mitigation of IL-6 release by a blinatumomab 5-15 µg/m²/day stepwise dosing regimen comparing to a 15 µg/m²/day flat dose. Our work provided a case example to show how mPBPK/PD model can be used to support the discovery and clinical development of T cell-redirecting bsAbs.

Keywords: Blinatumomab; Cytokine release; Minimal physiologically-based pharmacokinetic (mPBPK) model; Pharmacokinetic/pharmacodynamic (PK/PD) modeling; Stepwise dosing regimen; T cell redirecting bispecific antibodies (bsAbs).