A pre-clinical quantitative model predicts the pharmacokinetics/pharmacodynamics of an anti-BDCA2 monoclonal antibody in humans

BIIB059 is a novel humanized monoclonal antibody (mAb) that is currently under development for the treatment of Systemic Lupus Erythematosus and Cutaneous Lupus Erythematosus. BIIB059 is targeted against the blood dendritic cell antigen 2 (BDCA2), a receptor exclusively expressed on the surface of plasmacytoid dendritic cells (pDCs). Herein, we utilized pre-clinical pharmacokinetic (PK) and pharmacodynamic (PD) data to develop a non-human primate (NHP) model and to address whether the NHP model can be successfully scaled to predict the human PK/PD. In particular, PK data from 17 cynomolgus monkeys were utilized for PK model development, wherein BIIB059 was administered intravenously (1 and 10 mg/kg single-dosing and 5 mg/kg multiple-dosing) or subcutaneously (0.2 and 7.5 mg/kg single-dosing). Additionally, PD data (BDCA2 receptor density on pDCs) from 6 cynomolgus monkeys were used for the development of the PD model. The developed NHP two-compartment PK model, linked with an indirect response PD model, was subsequently scaled to humans by combining traditional allometric PK scaling with sensitivity-analysis-driven scaling of the PD. The scaled PK/PD model was then used to simulate the human PK/PD for different dose levels. When clinical data from the BIIB059 Phase I study became available, they were used to evaluate the predictability of the scaled PK/PD model and the model simulations were in agreement with the clinical data. Therefore, the presented approach is suggested to be employed in scaling pre-clinical mAb models to support the selection of safe first-in-human doses and, more broadly, the prediction of PK/PD in the clinic.