1. Anti-NKG2D single domain-based antibodies for the modulation of anti-tumor immune response
- Author
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Brigitte Kerfelec, Emmanuelle Vigne, Adeline Raynaud, Patrick Chames, Laurent Vidard, Klervi Desrumeaux, Elise Termine, Daniel Baty, 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), Sanofi [Vitry-sur-Seine], SANOFI Recherche, Kerfelec, Brigitte, Santé de la vigne et qualité du vin (SVQV), Université de Strasbourg (UNISTRA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)
- Subjects
0301 basic medicine ,NKG2D/NKG2DL axis ,[SDV]Life Sciences [q-bio] ,Immunology ,chemical and pharmacologic phenomena ,NK cells ,Epitope ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neoplasms ,HER2 ,Tumor Microenvironment ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,RC254-282 ,Original Research ,single-domain antibody ,biology ,Chemistry ,cell engagers ,Immunity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,RC581-607 ,Single-Domain Antibodies ,Natural killer T cell ,NKG2D ,3. Good health ,Cell biology ,Killer Cells, Natural ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Single-domain antibody ,Oncology ,NK Cell Lectin-Like Receptor Subfamily K ,030220 oncology & carcinogenesis ,biology.protein ,Immunologic diseases. Allergy ,Antibody ,[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy ,CD8 ,Research Article - Abstract
International audience; The natural killer group 2 member D (NKG2D) receptor is a C-type lectin-like activating receptor mainly expressed by cytotoxic immune cells including NK, CD8 + T, γδ T and NKT cells and in some pathological conditions by a subset of CD4 + T cells. It binds a variety of ligands (NKG2DL) whose expressions is finely regulated by stress-related conditions. The NKG2DL/NKG2D axis plays a central and complex role in the regulation of immune responses against diverse cellular threats such as oncogene-mediated transformations or infections. We generated a panel of seven highly specific anti-human NKG2D single-domain antibodies targeting various epitopes. These single-domain antibodies were integrated into bivalent and bispecific antibodies using a versatile plug-and-play Fab-like format. Depending on the context, these Fab-like antibodies exhibited activating or inhibitory effects on the immune response mediated by the NKG2DL/NKG2D axis. In solution, the bivalent anti-NKG2D antibodies that compete with NKG2DL potently blocked the activation of NK cells seeded on immobilized MICA, thus constituting antagonizing candidates. Bispecific anti-NKG2DxHER2 antibodies that concomitantly engage HER2 on tumor cells and NKG2D on NK cells elicited cytotoxicity of unstimulated NK in a tumor-specific manner, regardless of their apparent affinities and epitopes. Importantly, the bispecific antibodies that do not compete with ligands binding retained their full cytotoxic activity in the presence of ligands, a valuable property to circumvent immunosuppressive effects induced by soluble ligands in the microenvironment.
- Published
- 2020