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 proinflammatory cytokines in multiple in vivo mouse models while maintaining the antileukemia effect. Mechanistically, pegtarazimod reduced inflammation by decreasing ROS production, as investigated using allo-HCT recipient mice with genetic inactivation of NADPH oxidase in the BM. In addition to the antiinflammatory effect, pegtarazimod protected intestinal organoids against TNF-induced toxicity and oxidative DNA damage. In the phase II clinical trial AURORA, pegtarazimod treatment was well tolerated in patients with corticosteroid-refractory aGVHD (ClinicalTrials.gov NCT06343792), with an overall response rate of 4/7 patients at day 28. In summary, pegtarazimod reduced aGVHD in mice by suppressing proinflammatory 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)