Abstract
The success of allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (aGVHD). We have previously reported that neutrophils can exacerbate tissue damage caused by conditioning regimens. Pegtarazimod is a synthetic peptide, derived from the capsid protein of human astrovirus serotype 1, that was shown to reduce neutrophil effector functions. Therefore, we evaluated the therapeutic activity of pegtarazimod against aGVHD. Pegtarazimod significantly reduced aGVHD-related mortality, histological aGVHD severity, and pro-inflammatory cytokines in multiple in vivo mouse models, while maintaining the anti-leukemia effect. Mechanistically, pegtarazimod reduced inflammation by decreasing ROS production as investigated using allo-HCT recipient mice with genetic inactivation of NADPH oxidase (NOX2) in the bone marrow. In addition to the anti-inflammatory effect, pegtarazimod protected intestinal organoids against TNF-induced toxicity and oxidative DNA damage. In the phase-2 clinical trial AURORA, pegtarazimod treatment was well-tolerated in patients with corticosteroid-refractory (SR) aGVHD (NCT06343792) with an overall response rate (ORR) of 4/7 patients at day 28. In summary, pegtarazimod reduced aGVHD in mice by suppressing pro inflammatory neutrophil effector functions and preserving enterocyte integrity. The clinical trial data support tolerability of pegtarazimod in aGVHD patients and further studies are needed to determine efficacy.
Authors
Verena Holzmüller, Jana Gawron, Ann-Cathrin Burk, Anna-Verena Stell, Anna-Sophia Baur, Alexander Zähringer, Viktor Fetsch, Annika Mäder, Alina Hartmann, Nana Talvard-Balland, Neel Krishna, Kenji Cunnion, Ulrich Thienel, Paolo Martini, Lindsey Glenn, James L.M. Ferrara, Monzr M. Al Malki, Hannah Choe, José Antonio Pérez-Simón, Annette Schmitt-Graeff, Joerg Buescher, Natalie Köhler, Zohreh Mansoori Moghadam, Philipp Henneke, Geoffroy Andrieux, Melanie Boerries, Robert Zeiser
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ISSN: 0021-9738 (print), 1558-8238 (online)