Abstract 1617: Mechanistic modeling of a new kinetically-controlled CD122 agonist for cancer immunotherapy: NKTR-214 pharmacokinetics, pharmacodynamics, and receptor pharmacology
Authors: Khalili Samira , Odinecs Aleksandrs , Charych Deborah H. , Dixit Vidula , Kirk Peter , Chang Thomas , Langowski John , Rubas Werner , Doberstein Steve , Zalevsky Jonathan , Eldon Michael A. , Hoch Ute 
Published: July 2017

Abstract
Introduction: NKTR-214 is a biologic prodrug currently in a Phase 1 / 2 clinical trial in patients with solid tumors, as a single agent and in combination with anti-PD1. It is a CD122-biased cytokine agonist conjugated with multiple releasable chains of polyethylene glycol and designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand effector CD8+ T and NK cells over Tregs. Here we describe a mechanistic mathematical model that quantifies conjugated aldesleukin (IL-2) species that are generated from NKTR-214, their sustained exposure, and biased receptor pharmacology in rodent models.
Methods: A mechanistic mathematical model, using ordinary differential equations (ODE), was developed using Matlab® programming language to describe the dynamics of NKTR-214 PEG release, clearance, distribution, and receptor occupancy in vivo. The model was conditioned using experimental data for in vitro binding of unconjugated IL-2 and active conjugated IL-2 derived from NKTR-214 to IL-2 receptors using surface plasmon resonance, in vitro PEG release data, and mouse pharmacokinetics data. Simulations were performed to 1) quantify the concentration-time profiles of the various conjugated IL-2 species derived from NKTR-214 and contribution of each of them to the NKTR-214 mechanism of action, and 2) compare occupancy at IL-2Rβγ and IL-2Rαβγ receptors after administration of therapeutic doses of NKTR-214 and aldesleukin.
Results: After NKTR-214 administration, PEG chains are released slowly from the prodrug and active conjugated IL-2 species gradually increase and reach maximum concentrations about one day post-dose, followed by sustained exposure for up to a week. Compared to an equivalent dose of aldesleukin, the active conjugated IL-2 species derived from NKTR-214 achieve a 26-fold higher area under the curve (AUC) of IL-2Rβγ occupancy, and a 0.34-fold lower AUC of IL-2Rαβγ occupancy. The significant difference is due to the combined effects of slow release of active conjugated IL-2 species from NKTR-214 and their favorable binding kinetics towards IL-2Rβγ. Aldesleukin, even when simulated at repeated daily doses or constant infusion, is incapable of increasing the receptor occupancy at IL-2Rβγ without simultaneously increasing the receptor occupancy at IL-2Rαβγ in this model.
Conclusions: The mechanistic model demonstrated how NKTR-214’s intrinsic design enables both biased receptor pharmacology and sustained exposure in vivo. Such biased receptor binding could not be achieved by a sustained delivery of aldesleukin.
Citation Format: Samira Khalili, Aleksandrs Odinecs, Deborah H. Charych, Vidula Dixit, Peter Kirk, Thomas Chang, John Langowski, Werner Rubas, Steve Doberstein, Jonathan Zalevsky, Michael A. Eldon, Ute Hoch. Mechanistic modeling of a new kinetically-controlled CD122 agonist for cancer immunotherapy: NKTR-214 pharmacokinetics, pharmacodynamics, and receptor pharmacology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1617. doi:10.1158/1538-7445.AM2017-1617