Objectives: The balance of regulatory T cells (Tregs) and conventional T cells (Tcons) plays a crucial role in maintaining immune homeostasis and preventing autoimmune diseases. Low-dose Interleukin-2 (IL-2) therapy has emerged as a promising approach for modulating Treg activity in various immunotherapy settings. However, mechanistic understanding of how IL-2 influences Treg dynamics remains incomplete. MK-6194 is an IL-2 mutein that was designed as a specific biologic response modifier of Tregs through increasing the binding affinity for IL-2 receptor alpha chain (IL-2Rα or CD25) and reducing the binding affinity for IL-2Rβ but without effects on Tcons [1]. The objective of this study was to develop a minimal QSP model to explore the intricate mechanisms between IL-2 mutein and Treg expansion.
Methods: The development of the minimal QSP model involved four steps: (1) adapting an existing literature QSP IL-2 model [2] with the addition of IL-2 mutein, (2) reducing the adapted QSP model to include only essential components, (3) conducting identifiability and global sensitivity analyses to support estimation of parameters, and (4) parameter estimation including inter-individual variabilities (IIVs) using NONMEM.
Results: The final developed model consisted of 5 ordinary differential equations: (1) PK depot compartment, (2) PK central compartment, (3) compartment of Tregs, (4) compartment of sCD25 (soluble form of CD25), and (5) compartment of IL-2R on Tregs. Known mechanisms of IL-2 mediated Treg expansion and unique characteristics of MK-6194 were incorporated into the model structure. This includes MK-6194 binding to IL-2R, signaling of MK-6194/IL-2R complex for Treg proliferation, dynamic IL-2R density on Treg as well as the interaction of MK-6194 with sCD25. Furthermore, the model was used to explore tolerance of Treg response with chronic dosing via an added tolerance compartment for cumulative receptors reflecting changes in IL-2R density on Tregs. It was suspected that the tolerance might be caused by a potential imbalance of IL-2Rα and IL-2Rβγ on Tregs or down regulation of these receptors. Using the model, the effects of dose and dosing frequency on Treg changes over time were predicted, and the potential impacts of different dosing regimens on tolerance was also evaluated.
Conclusions: We have developed a minimal-QSP model to assess the complex interactions between regulatory T-cells and an IL-2 mutein. The model enhances our understanding to the dynamic multi-cell system governing Treg biology in IL-2 mutein therapy. As the model is driven by underlying mechanisms, it can be applied to the same class of compounds for dose optimization or hypothesis testing with a potential to accelerate immunotherapeutic discovery and development.
