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Background: Currently bispecific monoclonal antibodies gain traction in pharmacology as a way to simultaneously target different surface molecules on immune and tumor cells and modulate their activity. While antibodies against a single target, such as CD40 on antigen-presenting cells (APCs) and PD1 on T cells, are widely used in clinic to treat various forms of cancer, bispecific antibodies are still in the early stages of clinical development. The aim of this study was to predict pharmacokinetics (PK), receptor occupancy (RO) and optimal dose for a bispecific antibody YH008 against CD40 and PD1 using the PBPK/RO model. Methods: The PBPK/RO model describes distribution of an antibody (mAb) between physiological compartments, transport across the endothelium, binding with CD40 on dendritic cells (DCs), B cells, and macrophages (Mph) and PD1 on CD4+ and CD8+ T cells in the immunological synapses (ISs). The model takes into account number of cells expressing target molecules and their ligands, expression levels, clearance of the antibody. Two scenarios of mAb binding with CD40 were considered: a case when the mAb competes with CD40L for the binding site and a case when the mAb binds to a different site. Binding affinities of YH008 for human CD40 and PD1 were taken from [1]. The model was validated using PK data on monospecific antibodies against CD40 and PD1. ROs of PD1 on CD4+ and CD8+ T cells and CD40 for Mph, DCs, B cells and percentages of the trimer complex (CD40-YH008-PD1) were calculated. Optimal dose of YH008 was selected on the basis of maximal exposure/area under curve (AUC) of the trimers in ISs between APCs and CD8+ T cells in the tumor. Results: Model simulations show good agreement with the experimental PK and RO data for monospecific mAbs against PD1 (Pembrolizumab) and CD40 (Selicrelumab, BI 655064). For the bispecific antibody, the simulations show that competition for the CD40 binding site between CD40L and the mAb does not significantly affect PK and RO in blood or tissue. The model predicts 99% RO on antigen-presenting cells (APCs) and 98% RO on T cells in blood at dose 80 mg. In the tumor, 95% RO on APCs and 85% RO on T cells, as well as 5-to-6-fold decrease in the number of PD1-PDL1 complexes in ISs, are achieved at dose 240 mg. The dose dependence for YH008 was calculated, and the optimal dose based on the numbers of the trimers and signaling complexes in the ISs was estimated. Conclusions: The PBPK/RO model for a bispecific mAb based on physiological levels of immune cells, target molecule expression, and binding parameters for YH008 antibody against CD40 and PD1 predicts PK and RO in peripheral blood and tumor. The model shows that competition for CD40 binding site between the mAb and CD40L does not significantly affect PK and RO. The optimal dose for maximal effect of YH008 was estimated. Citation Format: Alexandra Diakonova, Oleg Demin, Dmitry Shchelokov, Oleg Demin. Prediction of pharmacokinetics and receptor occupancy of a bispecific antibody against CD40 and PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5049. |
