Leveraging quantitative systems pharmacology (QSP) modeling to understand effects of corticosteroids on immune cells and cytokine release following administration of SC Epcoritamab
Authors: Afzal Nasrin , Li Tommy , Putnins Mathew , Sanghavi Kinjal , Wielgos-Bonvallet Monica , Eskelund Christian , Steele Andrew , Sacchi Mariana , Gupta Manish , Xu Steven , Thalhauser Craig 
Published: February 2025

Objectives: Epcoritamab is a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ B cells, including CD20+ malignant cells (2). Cytokine release syndrome (CRS) is an adverse event of special interest for T cell engagers such as Epcoritamab. Step-up dosing (SUD) regimens have been investigated and optimized to minimize risk of CRS in EPCORE NHL-1 (NCT03625037). In addition, prophylactic corticosteroids were employed to moderate adaptive and innate immune cells, hence as an additional CRS mitigation strategy. The analysis's aim was to help understand the effects of prophylactic corticosteroids including dexamethasone and prednisolone on immune cells and cytokine release following administration of SC Epcoritamab by leveraging a QSP model. Methods: By utilizing both preclinical and clinical data of Epcoritamab, we have created a QSP platform that effectively assesses the pharmacodynamic (PD) markers associated with the chosen SUD regimen for efficacy and safety (1). A minimal physiologically based pharmacokinetics (PK)/PD (mPBPK/PD) model including submodels of T cell activation, proliferation, and cytotoxicity of target-bearing cells linked to QSP model (7-9), to create an integrated QSP model of the B-cell NHL system (3-6) and update the SUD dosing schedule. The corticosteroid QSP submodule integrates PK and PD of the corticosteroid in blood circulation, lymph node(s), tumor, and other peripheral body tissue. The study focused on the intended outcomes of corticosteroids on immune cells and cytokine release, utilizing a mPBPK/PD model alongside a corticosteroid compartmental model.Simulations were conducted to understand the relationship between corticosteroid regimen and model predicted outcomes. A virtual population was generated and calibrated to individual patient trajectories of plasma biomarkers and primary lesion response. Results: After subcutaneous administration of Epcoritamab, transient and modest elevation of selected cytokines was observed. The QSP model studied the impact of corticosteroids on cytokine production and cell proliferation. The characterized dynamics of cells stimulation and/or suppression and cytokine release by using the QSP model provide better insight on the pharmacological effects of prophylactic corticosteroids. Conclusions: This analysis integrated underlying mechanisms for understanding Epcoritamab and administered corticosteroids for B-cell NHL patients to mitigate CRS symptoms by using biomarkers such as IL6 and IL10. Citations: Afzal N. et al. AACR. 2023; 83:846.2. Engelberts PJ, et al. EBioMedicine. 2020;52:102625.3. Hutchings M, et al. Lancet. 2021;398:1157-69.4. Hosseini I, et al. NPJ Syst Biol Appl. 2020;6:28.5. Betts A, et al. AAPS J. 2019;21:66.6. Chen X, et al. CPT Pharmacometrics Syst Pharmacol. 2014;3:e134.7. Mager DE, et al, J Pharm Sci. 2003,92(7):1521-5.8. Yakimchuk K. Biosystems, 2020;187:104066.9. Ehrchen JM, et al. Front Immunol. 2019; 10.338