1. Unexpected cross-reactivity of anti-cathepsin B antibodies leads to uncertainties regarding the mechanism of action of anti-CD20 monoclonal antibody GA101
- Author
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Gilles Salles, Charlène Niogret, Abdel Aouacheria, Romain Jugé, Aurélie Cornut-Thibaut, Wei Wen Chien, Loïc Lionnard, Ariel Savina, Jérôme Kucharczak, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), and Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE)
- Subjects
Cancer Research ,[SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging ,MESH: Antibodies, Monoclonal/pharmacology ,MESH: Cathepsin B/immunology ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Humanized antibody ,Cathepsin B ,0302 clinical medicine ,[INFO.INFO-BT]Computer Science [cs]/Biotechnology ,CD20 ,MESH: Mitochondrial Membranes/metabolism ,biology ,Antibodies, Monoclonal ,Hematology ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Mitochondrial Membranes ,MESH: Antigens, CD20/immunology ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Lymphomas ,medicine.symptom ,Antibody ,Lysosomal permeabilization ,Cell death ,MESH: Cell Line, Tumor ,medicine.drug_class ,Antibody-based immunotherapy ,MESH: Intracellular Membranes/metabolism ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Cross Reactions ,Monoclonal antibody ,Antibodies, Monoclonal, Humanized ,MESH: Lysosomes/ultrastructure ,Permeability ,03 medical and health sciences ,MESH: Antibodies, Monoclonal, Humanized/pharmacokinetics ,Antigen ,Cell Line, Tumor ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,MESH: Antibodies, Monoclonal/immunology ,medicine ,Leukemia, B-Cell ,Humans ,MESH: Antibodies, Monoclonal, Humanized/therapeutic use ,GA101 ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,MESH: Leukemia, B-Cell/drug therapy ,MESH: Cross Reactions/immunology ,MESH: Humans ,MESH: Antibodies, Monoclonal/therapeutic use ,MESH: Permeability/drug effects ,Actin remodeling ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Intracellular Membranes ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,Antigens, CD20 ,MESH: Cell Death/drug effects ,Mechanism of action ,Immunology ,Cancer research ,biology.protein ,Lysosomes ,030215 immunology - Abstract
International audience; GA101, also known as obinutuzumab or Gazyva (Gazyvaro), is a glycoengineered type II humanized antibody that targets the CD20 antigen expressed at the surface of B-cells. This novel anti-CD20 antibody is currently assessed in clinical trials with promising results as a single agent or as part of therapeutic combinations for the treatment of B-cell malignancies. Detailed understanding of the mechanisms of GA101-induced cell death is needed to get insight into possible resistance mechanisms occurring in patients. Although multiple in vitro and in vivo mechanisms have been suggested to describe the effects of GA101 on B-cells, currently available data are ambiguous. The aim of our study was to clarify the cellular mechanisms involved in GA101-induced cell death in vitro, and more particularly the respective roles played by lysosomal and mitochondrial membrane permeabilization. Our results confirm previous reports suggesting that GA101 triggers homotypic adhesion and caspase-independent cell death, two processes that are dependent on actin remodeling and involve the production of reactive oxygen species. With respect to lysosomal membrane permeabilization (LMP), our data suggest that lack of specificity of available antibodies directed against cathepsin B may have confounded previously published results, possibly challenging current LMP-driven model of GA101 action mode.
- Published
- 2017
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