Pegtarazimod limits acute graft-versus-host disease mortality and severity in mice and is tolerated in patients
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
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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Research Article Hematology Immunology

Pegtarazimod limits acute graft-versus-host disease mortality and severity in mice and is tolerated in patients

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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Figure 7

Pegtarazimod protects enterocytes by decreasing DNA damage.

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Pegtarazimod protects enterocytes by decreasing DNA damage. (A–C) Gene e...
(A–C) Gene expression profiling of small intestinal organoids derived from BALB/c mice, challenged with TNF and treated with pegtarazimod or vehicle for 2 days (n = 5). (A) PCA based on log2 robust multiarray average normalized intensity of all genes. (B) Top 10 most downregulated [ranked by –log10(q value)] Gene Ontology Biological Process (GOBP) gene sets in the TNF + pegtarazimod group compared with the TNF + vehicle group. Bar color intensity represents the number of genes (NB) in the leading edge for each term (n = 5). (C) Heatmap showing the top 10 most downregulated genes of the GOBP term DNA damage response in the TNF + pegtarazimod group compared with the TNF + vehicle group. Colors represent row-wise z scores (left) and log2 fold changes (FC; right). Genes marked with an asterisk are significantly differentially expressed (adjusted P < 0.05). (D–F) MODE-K cells were challenged with menadione and treated with pegtarazimod or vehicle for 2 h, and expression of γH2A.X was assessed using IF staining of cells in a 96-well plate. (D) Schematic representation of cell density in the wells. Color gradient indicates relative cell counts (see scale). (E) Quantification of MODE-K cells expressing γH2A.X relative to the number of cells in the well (n = 11–12). P values were calculated using Kruskal-Wallis test with Dunn’s multiple-comparison test. (F) Representative images of IF staining for DAPI (blue) and γH2A.X (green). Scale bars: 20 μm.