Abstract
BackgroundIL-21 has been shown to play an important role in autoimmune diseases. ATR-107 is an antibody which directly targets the IL-21 receptor (IL-21R). To aid the clinical development of ATR-107, there is a need for understanding the mechanism of action (MOA) of this antibody when assessing target engagement in human subjects.MethodsTo determine ATR-107 biological activity and potency in human blood, its inhibitory function against IL-21 induced STAT3 phosphorylation in human peripheral T and B cells was measured.ResultsThe data show that IL-21 induces STAT3 phosphorylation in a concentration-dependent manner, consistent with its migration to the nuclear. Using a flow cytometry based functional whole blood assay, ATR-107 is demonstrated to be a potent IL-21 pathway inhibitor. It competes with IL-21 for receptor binding in a competitive manner, but once it binds to the receptor it behaves like a non-competitive inhibitor, most probably due to the long observed koff. The concentration-dependent inhibition observed with ATR-107 correlates inversely with the levels of receptor occupancy, both in ex vivo whole blood assays and directly in human blood when ATR-107 was given to healthy volunteers.ConclusionsIL-21 induced phosphorylation of STAT3 in T and B cells can be used as a biomarker to evaluate the target engagement of ATR-107 in human whole blood. The antibody behaves like a potent non-competitive inhibitor blocking IL-21 induced STAT3 phosphorylation for a long period of time. These results may help with the translation of preclinical information and dose selection towards ATR-107 clinical efficacy.
Highlights
Interleukin-21 (IL-21) is a recently discovered type I cytokine that modulates the proliferation and function of various cell types, including T cells, B cells and Natural Killer (NK) cells [1]
Since STAT3 is a direct downstream signal of IL-21 receptor (IL-21R) activation, and it plays a critical role in regulating immune responses [3,4,11,12,13], we sought to use STAT3 phosphorylation as a new pharmacodynamic biomarker to understand the mechanism of action of ATR-107
The activity of ATR-107 was further evaluated when present in human blood using flow cytometry, a technology which is capable of sorting out cell populations of interest without the need for cell isolation
Summary
Interleukin-21 (IL-21) is a recently discovered type I cytokine that modulates the proliferation and function of various cell types, including T cells, B cells and NK cells [1]. The IL-21 receptor The use of biomarkers in drug development is very important in understanding the mechanism of action, dose selection and patient stratification. Since STAT3 is a direct downstream signal of IL-21R activation, and it plays a critical role in regulating immune responses [3,4,11,12,13], we sought to use STAT3 phosphorylation as a new pharmacodynamic biomarker to understand the mechanism of action of ATR-107. IL-21 has been shown to play an important role in autoimmune diseases. ATR-107 is an antibody which directly targets the IL-21 receptor (IL-21R). To aid the clinical development of ATR-107, there is a need for understanding the mechanism of action (MOA) of this antibody when assessing target engagement in human subjects
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