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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
Author(s) -
Frohna Paul A.,
Ratnayake Anoshie,
Doerr Nick,
Basheer Asjad,
AlMawsawi Laith Q.,
Kim Woo Jae,
Zapata Juan C.,
Wu Xiaorong,
Waldmann Thomas A.,
Azimi Nazli,
Tagaya Yutaka
Publication year - 2020
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1522
Subject(s) - pharmacodynamics , cd8 , pharmacology , adverse effect , medicine , pharmacokinetics , flow cytometry , immunology , immune system
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.