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A QSP model to understand clinical cytokine dynamics following bispecific dosing in solid tumors

Jared Weddell, Ph.D.
Senior Manager, Clinical Pharmacology and Exploratory Development, Astellas Pharma US, Northbrook, IL

Cytokine release syndrome (CRS) is a common clinical adverse effect observed following CD3-based bispecific dosing. However, the pathophysiology of CRS is not fully understood, and no computational model mechanistically describing clinical cytokine dynamics following bispecific dosing in solid tumors exists. A quantitative systems pharmacology (QSP) model describing peripheral clinical cytokine dynamics following bispecific dosing in solid tumors is presented. Using tebentafusp as a case study, a CD3-bispecific approved for uveal melanoma, the QSP model captures biological phenomena such as cytokine attenuation using step-up dosing regimens and the importance of on-target off-tumor binding towards CRS. The QSP model additionally serves as a platform for other CD3-based bispecifics or tumor types, supporting applications including dose selection, candidate nomination, and disease area selection.