Abstract 2085: Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize tumor killing effect of an anti-VISTA monoclonal antibody in tumor bearing mice

Abstract

Abstract The V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a recently discovered co-inhibitory molecule that shares limited sequence homology with the IgV domain of immune regulators of the B7 family. A first-in-class monoclonal antibody (mAb) that targets VISTA is currently in development for evaluation in patients with non-small cell lung cancer and other types of cancer. Data from a preclinical mouse model (in human VISTA knock-in mice) showed that treatment with its surrogate antibody demonstrated tumor growth inhibition, which is believed to be associated with modulation of the myelomonocytic and T cell compartments. A mechanistic pharmacokinetic/ pharmacodynamic (PK/PD) modeling approach was applied that integrated the in vitro and in vivo information (PK, target occupancy (TO) and tumor growth), and incorporated key physiological processes. A one-compartment pharmacokinetic model with Michaelis-Menten elimination kinetics was used to characterize the nonlinear clearance of the surrogate antibody. The growth and killing of tumor cells was described with a cell distribution tumor growth/ killing model. Tumor killing effects can be described well by a linear relationship to VISTA TO. The developed PK/PD model captured the observed data in mice. This work also presents the potential of how mechanistic modeling and simulation can support first-in-human dose selection and dosing regimen optimization for immunomodulatory mAbs for anticancer immunotherapy. Citation Format: Xiling Jiang, Jocelyn Leu, Indrajeet Singh, Linda A. Snyder, Weirong Wang. Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize tumor killing effect of an anti-VISTA monoclonal antibody in tumor bearing mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2085.