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1. A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis

Author

Rutgeerts, Paul J, Fedorak, Richard N, Hommes, Daan W, Sturm, Andreas, Baumgart, Daniel C, Bressler, Brian, Schreiber, Stefan, Mansfield, John C, Williams, Marna, Tang, Meina, Visich, Jennifer, Wei, Xiaohui, Keir, Mary, Luca, Diana, Danilenko, Dimitri, Egen, Jackson, and O'Byrne, Sharon

Subjects
Inflammatory Bowel Disease, Biotechnology, Clinical Trials and Supportive Activities, Clinical Research, Digestive Diseases, Autoimmune Disease, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Adult, Aged, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Colitis, Ulcerative, Dose-Response Relationship, Drug, Double-Blind Method, Female, Gastrointestinal Agents, Humans, Infusions, Intravenous, Injections, Subcutaneous, Male, Middle Aged, Severity of Illness Index, Treatment Outcome, Young Adult, Etrolizumab, rhuMAb 7, ulcerative colitis, drug development, safety, pharmacokinetics, IBD clinical, IBD basic research, IBD, IBD models, apoptosis, cell cycle, immunology, inflammatory bowel disorders, dendritic cells, Crohn's disease, cytokines, genetics, signal transduction, IBD-genetics, antibody targeted therapy, arthritis, autoimmune disease, integrins, IBD–genetics, rhuMAb β7, Clinical Sciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology
Abstract

ObjectiveEtrolizumab (rhuMAb β7, anti-β7, PRO145223) is a humanised monoclonal antibody targeting the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC.DesignIn the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD).ResultsIn the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of β7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively.ConclusionEtrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.

Published
2013

2. CARD9 in neutrophils protects from colitis and controls mitochondrial metabolism and cell survival

Author

Camille Danne, Chloé Michaudel, Jurate Skerniskyte, Julien Planchais, Aurélie Magniez, Allison Agus, Marie-Laure Michel, Bruno Lamas, Gregory Da-Costa, Madeleine Spatz, Cyriane Oeuvray, Chloé Galbert, Maxime Poirier, Yazhou Wang, Alexia Lapiere, Nathalie Rolhion, Tatiana Ledent, Cédric Pionneau, Solenne Chardonnet, Floriant Bellvert, Edern Cahoreau, Amandine Rocher, Rafael Jose Argüello, Carole Peyssonnaux, Sabine Louis, Mathias L. Richard, Philippe Langella, Jamel El-Benna, Benoit Marteyn, Harry Sokol, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris Center for Microbiome Medicine (FHU PaCeMM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), MetaboHUB-MetaToul, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaToul FluxoMet (TBI-MetaToul), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut d’Etudes Avancées de l’Université de Strasbourg - Institute for Advanced Study (USIAS), Université de Strasbourg (UNISTRA), Pathogénèse des Infections vasculaires / Pathogenesis of Vascular Infections, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Funding was provided by the ANR-17-CE15-0019-01 grant and a Marie Skłodowska-Curie Actions fellowship., ANR-17-CE15-0019,MARYLAND,Modulation par Card9 du microbiote intestinal et de sa production d'agonistes Aryl hydrocarbon receptor: mécanisme, potentiel thérapeutique et comme biomarqueur dans les maladies inflammatoires chroniques de l'intestin(2017), LAMAS, Bruno, Modulation par Card9 du microbiote intestinal et de sa production d'agonistes Aryl hydrocarbon receptor: mécanisme, potentiel thérapeutique et comme biomarqueur dans les maladies inflammatoires chroniques de l'intestin - - MARYLAND2017 - ANR-17-CE15-0019 - AAPG2017 - VALID, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MetaToul-MetaboHUB, Institut Cochin, INSERM, CNRS, Université de Paris, Laboratoire d'excellence GR-Ex, Institut Cochin, INSERM, CNRS, UNiversité de Paris, Laboratoire d'excellence GR-Ex, Institut Pasteur, Université de Paris, Inserm 1225 Unité de Pathogenèse des infections Vasculaires, Métabolomique et Fluxomique (MetaToul) (TBI-MetaToul), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Faculte de Medecine Xavier Bichat, Université Paris Diderot - Paris 7 (UPD7), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, IBD, Gastroenterology, Apoptosis, [SDV.TOX.TCA]Life Sciences [q-bio]/Toxicology/Toxicology and food chain, mitochondrial activity, Gastrointestinal immune response, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, neutrophils, [SDV.TOX.TCA] Life Sciences [q-bio]/Toxicology/Toxicology and food chain, [SDV.TOX]Life Sciences [q-bio]/Toxicology, IBD-Genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology, gut inflammation, CARD9, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

ObjectivesInflammatory bowel disease (IBD) results from a combination of genetic predisposition, dysbiosis of the gut microbiota and environmental factors, leading to alterations in the gastrointestinal immune response and chronic inflammation. Caspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. However, the cell types and mechanisms involved in the CARD9 protective role against inflammation remain unknown.DesignWe used dextran sulfate sodium (DSS)-induced and adoptive transfer colitis models in total and conditional CARD9 knock-out mice to uncover which cell types play a role in the CARD9 protective phenotype. The impact of Card9 deletion on neutrophil function was assessed by an in vivo model of fungal infection and various functional assays, including endpoint dilution assay, apoptosis assay by flow cytometry, proteomics and real time bioenergetic profile analysis (Seahorse).ResultsLymphocytes are not intrinsically involved in the CARD9 protective role against colitis. CARD9 expression in neutrophils, but not in epithelial or CD11c+ cells, protects against DSS-induced colitis. In the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment. The decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation.ConclusionThese results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation, paving the way for new therapeutic strategies targeting neutrophils.Summary boxWhat is already known about this subject?Inflammatory bowel disease (IBD) results from genetic predisposition, microbiota dysbiosis and environmental factors, but the alterations of the immune response leading to chronic intestinal inflammation are still not fully understood.Caspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection.However, the cell types and cellular mechanisms involved in the CARD9 protective role against inflammation remain unknown.What are the new findings?CARD9 expression in neutrophils, but not in lymphocytes, epithelial cells or CD11c+ cells, protects against DSS-induced colitis.In the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment.The decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation.How might it impact on clinical practice in the foreseeable future?These results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation.Understanding the role of neutrophils in chronic inflammation could lead to innovative therapeutic strategies targeting these key immune cells for various complex diseases.

Published
2022
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3. Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes

Author

A E Wiskin, Claire Willis, Nadeem A. Afzal, Andrew Collins, Katja Christodoulou, Sarah Ennis, Jane Gibson, R Mark Beattie, Michael A. Simpson, John W. Holloway, William J. Tapper, and Rosanna Upstill-Goddard

Subjects
Male, Candidate gene, Adolescent, crohn's disease, DNA Mutational Analysis, Nod2 Signaling Adaptor Protein, Human leukocyte antigen, Biology, Bioinformatics, paediatric gastroenterology, Frameshift mutation, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Gene Frequency, Genetic predisposition, Humans, Computer Simulation, Exome, Genetic Predisposition to Disease, Age of Onset, Child, Allele frequency, Genetic Association Studies, Exome sequencing, ulcerative colitis, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, zollinger ellison syndrome, Models, Genetic, Inflammatory Bowel Disease, IBD-genetics, Gastroenterology, Inflammatory Bowel Diseases, 3. Good health, Phenotype, Child, Preschool, Mutation, Colitis, Ulcerative, Female, 030211 gastroenterology & hepatology, Common disease-common variant
Abstract

Background Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. Objective To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. Design DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. Results Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of

Published
2012
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4. A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis

Author

Stefan Schreiber, Richard N. Fedorak, Mary E. Keir, Daan W. Hommes, Sharon O'Byrne, Meina Tang, Daniel C. Baumgart, Diana Luca, Paul Rutgeerts, John C. Mansfield, Brian Bressler, Andreas Sturm, Dimitri Danilenko, Marna Williams, Xiaohui Wei, Jackson G. Egen, and Jennifer Visich

Subjects
Male, Ulcerative, Gastroenterology, rhuMAb 7, Severity of Illness Index, immunology, Monoclonal, Medicine, Etrolizumab, genetics, Stage (cooking), IBD models, Infusions, Intravenous, Humanized, Subcutaneous, apoptosis, Antibodies, Monoclonal, Crohns disease, Middle Aged, Colitis, Ulcerative colitis, inflammatory bowel disorders, Phase i study, Crohn's disease, Treatment Outcome, arthritis, 6.1 Pharmaceuticals, Cohort, cell cycle, Female, Drug, IBD–genetics, Intravenous, pharmacokinetics, signal transduction, Biotechnology, safety, Adult, medicine.medical_specialty, Infusions, Adolescent, Injections, Subcutaneous, Clinical Trials and Supportive Activities, IBD, Clinical Sciences, autoimmune disease, Placebo, Antibodies, Monoclonal, Humanized, Antibodies, Injections, Dose-Response Relationship, Paediatrics and Reproductive Medicine, Young Adult, Pharmacokinetics, Double-Blind Method, Gastrointestinal Agents, Clinical Research, Internal medicine, Humans, dendritic cells, Adverse effect, ulcerative colitis, Aged, Gastroenterology & Hepatology, Dose-Response Relationship, Drug, business.industry, Inflammatory Bowel Disease, IBD-genetics, Evaluation of treatments and therapeutic interventions, rhuMAb β7, medicine.disease, drug development, cytokines, Surgery, antibody targeted therapy, IBD clinical, IBD basic research, integrins, Colitis, Ulcerative, Digestive Diseases, business
Abstract

Objective Etrolizumab (rhuMAb β7, anti-β7, PRO145223) is a humanised monoclonal antibody targeting the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC. Design In the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD). Results In the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of β7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively. Conclusion Etrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.

Published
2012

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