Mechanistically modeling peripheral cytokine dynamics following bispecific dosing in solid tumors.

Bispecific antibodies exhibit proven clinical benefit, and many bispecifics are currently in clinical development for oncology. 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. Here, 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 model successfully captures the dynamics of five cytokines. The QSP model was shown to predict observed phenomena, such as cytokine maximum concentration suppression using step-up dosing regimens and the importance of on-target off-tumor binding toward CRS and toxicity. Furthermore, the QSP model provides rationale for these biological phenomena based on dynamics of immune cell activation and desensitization in tumors and healthy tissues. Overall, the QSP model structure presented here serves as a basis to infer cytokine dynamics for other CD3-based bispecifics or tumor types by altering model parameters to capture the scenario of interest, supporting applications including dose selection, candidate nomination, and disease area selection.