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.
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