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Results From a First‐in‐Human Study of BNZ‐1, a Selective Multicytokine Inhibitor Targeting Members of the Common Gamma (γc) Family of Cytokines

P. Frohna,A. Ratnayake,N. Doerr,A. Basheer,Laith Q. Al‐Mawsawi,W. Kim,J. Zapata,Xiaorong Wu,T. Waldmann,N. Azimi,Y. Tagaya

Published 2020 in Journal of clinical pharmacology

ABSTRACT

Pathologic roles of interleukin (IL)‐2, IL‐9, and IL‐15, have been implicated in multiple T‐cell malignancies and autoimmune diseases. BNZ‐1 is a selective and simultaneous inhibitor of IL‐2, IL‐9, and IL‐15, which targets the common gamma chain signaling receptor subunit. In this first‐in‐human study, 18 healthy adults (n = 3/cohort) received an intravenous dose of 0.2, 0.4, 0.8, 1.6, 3.2, or 6.4 mg/kg infused over ≤5 minutes on day 1 and were followed for 30 days for safety and pharmacokinetic/pharmacodynamic sample collection. No dose‐limiting toxicities, infusion reactions, or serious or severe treatment‐emergent adverse events were observed. Headache was the only treatment‐emergent adverse event in >1 subject (n = 3). Peak and total BNZ‐1 exposure was generally dose proportional, with a terminal elimination half‐life of ∼5 days. Pharmacodynamic effects of BNZ‐1 on regulatory T cells (Tregs, IL‐2), natural killer (NK) cells (IL‐15) and CD8 central memory T cells (Tcm, IL‐15) were measured by flow cytometry and used to demonstrate target engagement. For Tregs, 0.2 mg/kg was an inactive dose, while a maximum ∼50% to 60% decrease from baseline was observed on day 4 after doses of 0.4 to 1.6 mg/kg, and higher doses produced an 80% to 93% decrease from baseline on day 15. Similar pharmacodynamic trends were observed for natural killer cells and CD8 Tcm, although decreases in CD8 Tcm were more prolonged. These subpopulations returned to/toward baseline by day 31. T cells (total, CD4, and CD8), B cells, and monocytes were unchanged throughout. These preliminary results suggest that BNZ‐1 safely and selectively inhibits IL‐2 and IL‐15, which results in robust, reversible immunomodulation.

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