The DAV132 colon-targeted adsorbent does not interfere with plasma concentrations of antibiotics but prevents antibiotic-related dysbiosis: a randomized phase I trial in healthy volunteers

Meriem Messaoudene, Stéphanie Ferreira, Nathalie Saint-Lu, Mayra Ponce, Caroline Truntzer, Romain Boidot, Clément Bescop, Thomas Loppinet, Tanguy Corbel, Céline Féger, Karine Bertrand, Arielle Elkrief, Morten Isaksen, Fabien Vitry, Frédérique Sablier-Gallis, Antoine Andremont, Lloyd Bod, François Ghiringhelli, Jean Gunzburg and Bertrand Routy ()
Additional contact information
Meriem Messaoudene: Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)
Stéphanie Ferreira: Da Volterra
Nathalie Saint-Lu: Da Volterra
Mayra Ponce: Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)
Caroline Truntzer: Georges François Leclerc Cancer Center-Unicancer
Romain Boidot: Georges François Leclerc Cancer Center-Unicancer
Clément Bescop: Da Volterra
Thomas Loppinet: Da Volterra
Tanguy Corbel: Da Volterra
Céline Féger: Da Volterra
Karine Bertrand: Da Volterra
Arielle Elkrief: Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)
Morten Isaksen: Bio-Me
Fabien Vitry: Da Volterra
Frédérique Sablier-Gallis: Da Volterra
Antoine Andremont: Da Volterra
Lloyd Bod: Massachusetts General Hospital, Harvard Medical School
François Ghiringhelli: Georges François Leclerc Cancer Center-Unicancer
Jean Gunzburg: Da Volterra
Bertrand Routy: Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract The deleterious impact of antibiotics (ATB) on the microbiome negatively influences immune checkpoint inhibitors (ICI) response in patients with cancer. We conducted a randomized phase I study (EudraCT:2019-A00240-57) with 148 healthy volunteers (HV) to test two doses of DAV132, a colon-targeted adsorbent, alongside intravenous ceftazidime-avibactam (CZA), piperacillin-tazobactam (PTZ) or ceftriaxone (CRO) and a group without ATB. The primary objective of the study was to assess the effect of DAV132 on ATB plasma concentrations and both doses of DAV132 did not alter ATB levels. Secondary objectives included safety, darkening of the feces, and fecal ATB concentrations. DAV132 was well tolerated, with no severe toxicity and similar darkening at both DAV132 doses. DAV132 led to significant decrease in CZA or PTZ feces concentration. When co-administered with CZA or PTZ, DAV132 preserved microbiome diversity, accelerated recovery to baseline composition and protected key commensals. Fecal microbiota transplantation (FMT) in preclinical cancer models in female mice from HV treated with CZA or PTZ alone inhibited anti–PD-1 response, while transplanted samples from HV treated with ATB + DAV132 circumvented resistance to anti–PD-1. This effect was linked to activated CD8+ T cell populations in the tumor microenvironment. DAV132 represents a promising strategy for overcoming ATB-related dysbiosis and further studies are warranted to evaluate its efficacy in cancer patients.

Date: 2024
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DOI: 10.1038/s41467-024-52373-8

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