Towards a platform quantitative systems pharmacology (QSP) model for preclinical to clinical translation of antibody drug conjugates (ADCs).

A next generation multiscale quantitative systems pharmacology (QSP) model for antibody drug conjugates (ADCs) is presented, for preclinical to clinical translation of ADC efficacy. Two HER2 ADCs (trastuzumab-DM1 and trastuzumab-DXd) were used for model development, calibration, and validation. The model integrates drug specific experimental data including in vitro cellular disposition data, pharmacokinetic (PK) and tumor growth inhibition (TGI) data for T-DM1 and T-DXd, as well as system specific data such as properties of HER2, tumor growth rates, and volumes. The model incorporates mechanistic detail at the intracellular level, to account for different mechanisms of ADC processing and payload release. It describes the disposition of the ADC, antibody, and payload inside and outside of the tumor, including binding to off-tumor, on-target sinks. The resulting multiscale PK model predicts plasma and tumor concentrations of ADC and payload. Tumor payload concentrations predicted by the model were linked to a TGI model and used to describe responses following ADC administration to xenograft mice. The model was translated to humans and virtual clinical trial simulations were performed that successfully predicted progression free survival response for T-DM1 and T-DXd for the treatment of HER2+ metastatic breast cancer, including differential efficacy based upon HER2 expression status. In conclusion, the presented model is a step toward a platform QSP model and strategy for ADCs, integrating multiple types of data and knowledge to predict ADC efficacy. The model has potential application to facilitate ADC design, lead candidate selection, and clinical dosing schedule optimization.

How does ascorbate improve endothelial dysfunction? - A computational analysis.

Low levels of ascorbate (Asc) are observed in cardiovascular and neurovascular diseases. Asc has therapeutic potential for the treatment of endothelial dysfunction, which is characterized by a reduction in nitric oxide (NO) bioavailability and increased oxidative stress in the vasculature. However, the potential mechanisms remain poorly understood for the Asc mitigation of endothelial dysfunction. In this study, we developed an endothelial cell based computational model integrating endothelial cell nitric oxide synthase (eNOS) biochemical pathway with downstream reactions and interactions of oxidative stress, tetrahydrobiopterin (BH4) synthesis and biopterin ratio ([BH4]/[TBP]), Asc and glutathione (GSH). We quantitatively analyzed three Asc mediated mechanisms that are reported to improve/maintain endothelial cell function. The mechanisms include the reduction of •BH3 to BH4, direct scavenging of superoxide (O2•-) and peroxynitrite (ONOO-) and increasing eNOS activity. The model predicted that Asc at 0.1-100 µM concentrations improved endothelial cell NO production, total biopterin and biopterin ratio in a dose dependent manner and the extent of cellular oxidative stress. Asc increased BH4 availability and restored eNOS coupling under oxidative stress conditions. Asc at concentrations of 1-10 mM reduced O2•- and ONOO- levels and could act as an antioxidant. We predicted that glutathione peroxidase and peroxiredoxin in combination with GSH and Asc can restore eNOS coupling and NO production under oxidative stress conditions. Asc supplementation may be used as an effective therapeutic strategy when BH4 levels are depleted. This study provides detailed understanding of the mechanism responsible and the optimal cellular Asc levels for improvement in endothelial dysfunction.

The role of glutathione and glutathione peroxidase in regulating cellular level of reactive oxygen and nitrogen species.

Glutathione (GSH) and GSH/glutathione peroxidase (GPX) enzyme system is essential for normal intracellular homeostasis and gets disturbed under pathophysiologic conditions including endothelial dysfunction. Overproduction of reactive oxidative species (ROS) and reactive nitrogen species (RNS) including superoxide (O2•-), and the loss of nitric oxide (NO) bioavailability is a characteristic of endothelial dysfunction. The GSH/GPX system play an important role in eliminating ROS/RNS. Studies have provided important information regarding the interactions of ROS/RNS with the GSH/GPX in biological systems; however, it is not clear how this cross talk affect these reactive species and GSH/GPX enzyme system, under physiologic and oxidative/nitrosative stress conditions. In the present study, we developed a detailed endothelial cell kinetic model to understand the relationship amongst the key enzyme systems including GSH, GPX, peroxiredoxin (Prx) and reactive species, such as hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and dinitrogen trioxide (N2O3). Our simulation results showed that the alterations in the generation rates of O2•- and NO led to the formation of a wide range of ROS and RNS. Simulations performed by varying the ratio of O2•- to NO generation rates as well as GSH and GPX concentrations showed that the GPX reducing capacity was dependent on GSH availability, level of oxidative/nitrosative stress, and can be attributed to N2O3 levels, but not to H2O2 and ONOO-. Our results showed that N2O3 mediated switch-like depletion in GSH and the incorporation of Prx had no considerable effect on the ROS/RNS species other than ONOO- and H2O2. The analysis presented in this study will improve our understanding of vascular diseases in which the levels and oxidation states of GSH, GPX and/or Prx are significantly altered and pharmacological interventions show limited benefits.