(M-010) Quantitative system pharmacology model for tri-specific HER2xCD3xCD28 T-Cell Engager SAR443216

Faiza Rharbaoui, n/a – Business Title Clinical Expert in Pharmacokinetics, Pharmacokinetics/Pharmacodynamics, Translational Medicine and Early Development, Sanofi R&D, Frankfurt, Sanofi; Serena Masciari, n/a – Global Project Head, Oncology Immune Cell Engagers & Small Molecules, 3Earlyl Development, Clinical Sciences, Sanofi R&D, Cambridge, Sanofi; Lei Wang, n/a – Translational Precision Medicine Lead Neuro, Rare, Rare Blood Disorders, Precision Medicine Neuro, Rare, Rare Blood Disorders, Translational Medicine and Early Development, Sanofi R&D, Cambridge, Sanofi

Objectives: SAR443216 is a tri-specific antibody targeting human epidermal growth factor receptor 2 (HER2)-expressing tumors. SAR443216 functions as a T cell engager (TCE) with anti-CD3, -CD28 and -HER2 sites capable of simultaneously engaging respective cell-specific membrane receptor proteins. The drug mediates pharmacological actions by forming synaptic bridges between CD3+/CD28+ T cells and HER2+ tumor cells. Formation of synapses leads to the activation of cytotoxic T cells followed by tumor cell killing by the activated T cells. This killing process also accompanies a variety of cytokine release that induce more T cell activation and tumor cell killing. Because of this complex mechanism of action (MoA), which involves intricate interactions among molecules and cells, it is interesting to conceptually understand the safety and therapeutic efficacy of SAR443216. A quantitative systems pharmacology (QSP) model is developed to characterize key factors governing the safety and efficacy profiles of SAR443216.

Methods: A multiscale approach is taken to develop the QSP model for SAR443216. The multiscale model connects the drug’s pharmacokinetics to its MoA at the molecular and cellular scale to mechanistically explain its ex-vivo and in vivo pharmacological effects. The model explicitly incorporates cellular and molecular species representing T cells, tumor cells, and cell-specific membrane receptor proteins (CD3, CD28 and HER2). The molecular and cellular interactions included in the model capture the process of synapse formation between T cells and target cells, T cell activation and tumor cell killing. The model also accounts for a variety of cytokine biomarkers that characterize the compound's safety profile. The model is calibrated with a rich set of in-house data from in vitro and preclinical studies.

Results: 1) The QSP model captured pharmacological effects of SAR443216 on different tumor cell lines with various levels of HER2 expression. Associated simulations led to the identification of factors governing the ex-vivo cytotoxicity response profile of SAR443216. 2) The model captured SAR443216 dose-dependent T cell activation and cytokine release profiles for tumor cell lines with variable target (Her2) expression. These simulations identified biological variables dictating ex-vivo cytokine response profiles of SAR443216. 3) The model characterized in vivo dose to response relationships for SAR443216-induced cytokine responses in cynomolgus monkeys. The simulations provided insights into the safety response profiles directly linked to the drug MoA or non-specific sources.

Conclusions: The QSP model has served as a computational platform to test and validate SAR443216 MoA and its response characteristics in vitro and in vivo preclinical settings. The platform will serve as a foundation for modeling other emerging tri specific TCEs with similar MoA.

Citations: N/A