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. 2020 Aug 28;6:28. doi: 10.1038/s41540-020-00145-7

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — The QSP model was calibrated using multiple dose preclinical data of E. coli produced anti-CD20/CD3 TDB in cynomolgus monkeys (preclinical study 1, 0.01–1 mg/kg). The outcome was a reference virtual cyno, which reproduces the dynamics of cytokines, B and T-cells in the PB and lymphoid tissues. The model was then validated against data from the single-dose mosunetuzumab in cynomolgus monkeys (preclinical study 2, 0.001–0.1 mg/kg) by using the reference virtual cyno to predict the B and T-cell profiles. Next, the reference virtual cyno was translated to the human ALL patient using the appropriate physiological volume and T and B-cell numbers for different tissues and including blinatumomab PK and its downstream effects on T-cell activation and B-cell killing. The model was successfully validated against the clinical data from blinatumomab in ALL patients. In addition, we used reference virtual cyno and human models to validate the cytokine hypothesis by predicting the IL6 Levels measured in chimpanzees treated with multiple weekly injections of blinatumomab (preclinical study 4). To capture the observed variability in cyno measurements, we generated a virtual cohort of healthy cynos using the range of observed measurements in the multiple dose study of mosunetuzumab in cynomolgus monkeys (preclinical study 1) and validated against the single-dose mosunetuzumab in cynomolgus monkeys (Preclinical study 3, 0.01–1.0 mg/kg). We generated a virtual NHL population by translating the virtual cohort of healthy cynos, adding a tumor compartment by implementing a large B-cell dense mass using human physiology and including additional disease-related variability such as baseline peripheral B and T-cells, tumor load, tumor cell doubling time and revised B:T ratio in the tumor microenvironment. The virtual NHL population matched the distribution of antitumor efficacy and cytokine time profiles following blinatumomab treatment. This population was subsequently used to predict and compare the time course of systemic cytokine levels and antitumor efficacy for different dosing regimens of mosunetuzumab.