Ji, Yan, Chen, Heller, Knee, Deborah, Dang, Anhthu, Mataraza, Jennifer, Wolf, Babette and Sy, Sherwin (2022) Model-informed drug development for immuno-oncology agonistic anti-GITR antibody GWN323: MABEL-based dose selection, translational and clinical PK/PD modeling. Clinical and translational science.

Abstract

GWN323, an agonistic human anti-GITR (glucocorticoid-induced TNFR-related protein) IgG1 antibody, was studied clinically as an immuno-oncology therapeutic agent. A model-based minimum anticipated biological effect level (MABEL) approach integrating in vitro and in vivo data was used to inform dose selection for the first-in-human (FIH) study in patients with cancer. Data evaluated included the pharmacokinetics (PK), soluble GITR (sGITR) and tumor shrinkage in Colon26 syngeneic mice administered with DTA-1.mIgG2a (a mouse surrogate GITR antibody), cytokine release of GWN323 in human peripheral blood mononuclear cells, GITR binding affinity, and GWN323 PK exposure at the highest non-severe toxic dose in monkeys. A PK model was developed to describe DTA-1.mIgG2a PK and the relationship between DTA-1.mIgG2a exposure and sGITR was also modeled. Human GWN323 PK was predicted by allometric scaling of mouse PK. Based on the totality of PK/PD modeling and the in vitro and in vivo pharmacology and toxicology data, MABEL was estimated and informed the starting dose selection of the FIH study. Based on tumor kinetic PK/PD modelling of tumor inhibition by DTA-1.mIgG2a in Colon26 mice and the predicted human PK of GWN323, the biologically active dose of GWN323 was predicted and informed dose escalation of the FIH study. GWN323 PK from the FIH study was described by a population PK model and the relationship between ex vivo interleukin-2 release, a target-engagement marker, and GWN323 concentration was also modeled. The clinical PK/PD modeling data supported the biological active dose predicted from the translational PK/PD modeling in a “learn and confirm” paradigm of model-informed drug development of GWN323.

Item Type:	Article
Date Deposited:	16 Aug 2022 00:46
Last Modified:	16 Aug 2022 00:46
URI:	https://oak.novartis.com/id/eprint/47072