Development of ICT01, a first-in-class, anti-BTN3A antibody for activating Vγ9Vδ2 T cell–mediated antitumor immune response
| Autor: | Noémie Joalland, Paul Frohna, Magali Colazet, Patrick Brune, René Hoet, Emmanuel Scotet, Daniel Olive, Jaime Guillén, Carla E. Cano, Clément Ghigo, Sophie Agaugué, Kieu-Suong Le, Johann De Bonno, Alemseged Truneh, Rémy Castellano, Jennifer S. Sims, Armelle Goubard, Emmanuel Valentin, Christine Pasero, Aurélien Marabelle, Yves Collette, Aude De Gassart |
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| Přispěvatelé: | ImCheck Therapeutics [Marseille], Integrated Biologix GmbH [Basel, Switzerland], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), TrGET Platform, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Université Paris-Saclay, The institute of cancer research [London], Maastricht University [Maastricht], Bernardo, Elizabeth, Pathologie, RS: FHML non-thematic output |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
GENES
T cell T-Lymphocytes Tumor cells [SDV.CAN]Life Sciences [q-bio]/Cancer Lymphocyte Activation PHOSPHOANTIGEN Immune system [SDV.CAN] Life Sciences [q-bio]/Cancer Antigen medicine Cytotoxic T cell CYTOTOXICITY IMMUNOTHERAPY Receptor biology Chemistry Receptors Antigen T-Cell gamma-delta General Medicine medicine.anatomical_structure Cancer research Lymphocyte activation biology.protein Antibody BUTYROPHILIN BTN TCR |
| Zdroj: | Science Translational Medicine Science Translational Medicine, 2021, 13 (616), ⟨10.1126/scitranslmed.abj0835⟩ Science Translational Medicine, 13(616):eabj0835. American Association for the Advancement of Science |
| ISSN: | 1946-6234 1946-6242 |
| DOI: | 10.1126/scitranslmed.abj0835⟩ |
| Popis: | Gamma delta T (gamma delta T) cells are among the most potent cytotoxic lymphocytes. Activating anti-butyrophilin 3A (BTN3A) antibodies prime diverse tumor cell types to be killed by V gamma 9V delta 2 T cells, the predominant gamma delta T cell subset in peripheral circulation, by mechanisms independent of tumor antigen-major histocompatibility complex (MHC) complexes. In this report, we describe the development of a humanized monoclonal antibody, ICT01, with sub-nanomolar affinity for the three isoforms of BTN3A. We demonstrate that ICT01-activated V gamma 9V delta 2 T cells kill multiple tumor cell lines and primary tumor cells, but not normal healthy cells, in an efficient process requiring approximately 20% target occupancy. We show that ICT01 activity is dependent on BTN3A and BTN2A but independent of the phosphoantigen (pAg)-binding B30.2 domain. ICT01 delays the growth of hematologic and solid tumor xenografts and prolongs survival of NOD/SCID/IL2r gamma(null) (NSG) mice adoptively transferred with human V gamma 9V delta 2 T cells. In single- and multiple-dose safety studies in cynomolgus macaques that received up to 100 mg/kg once weekly, ICT01 was well tolerated. With respect to pharmacodynamic endpoints, ICT01 selectively activated V gamma 9V delta 2 T cells without affecting other BTN3A-expressing lymphocytes such as alpha beta T or B cells. A first-in-human, phase 1/2a, open-label, clinical study of ICT01 was thus initiated in patients with advanced-stage solid tumors (EVICTION: NCT04243499; EudraCT: 2019-003847-31). Preliminary results show that ICT01 was well tolerated and pharmacodynamically active in the first patients. Digital pathology analysis of tumor biopsies of a patient with melanoma suggests that ICT01 may promote immune cell infiltration within the tumor microenvironment. |
| Databáze: | OpenAIRE |
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