Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity

• Published in: Cell Vol. 177; no. 7; pp. 1701 - 1713.e16
• Main Authors: Gauthier, Laurent, Morel, Ariane, Anceriz, Nadia, Rossi, Benjamin, Blanchard-Alvarez, Audrey, Grondin, Gwendoline, Trichard, Sylvia, Cesari, Cédric, Sapet, Melody, Bosco, Frédéric, Rispaud-Blanc, Hélène, Guillot, Franceline, Cornen, Stéphanie, Roussel, Alain, Amigues, Béatrice, Habif, Guillaume, Caraguel, Flavien, Arrufat, Sandrine, Remark, Romain, Romagné, François, Morel, Yannis, Narni-Mancinelli, Emilie, Vivier, Eric
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.06.2019; Elsevier
• Subjects: animal models; Animals; antibodies; Antibodies, Bispecific - immunology; Antibodies, Bispecific - therapeutic use; antigens; Antigens, Ly - immunology; Antineoplastic Agents, Immunological - immunology; Antineoplastic Agents, Immunological - pharmacology; cancer immunotherapy; Cytotoxicity, Immunologic - drug effects; Humans; immunity; immunoglobulin G; Immunoglobulin G - immunology; Immunoglobulin G - pharmacology; Immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Life Sciences; Mice; monoclonal antibodies; Natural Cytotoxicity Triggering Receptor 1 - immunology; natural killer cells; neoplasm cells; neoplasms; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; pharmacokinetics; receptors; T-lymphocytes; therapeutics; toxicity; natural killer cells; cancer immunotherapy; monoclonal antibodies
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.04.041

Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor T cell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent in vitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar in vivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer. [Display omitted] [Display omitted] •NK cell engagers are multifunctional Abs targeting tumor antigens, NKp46 and CD16•NKCEs bring tumor cells and NK cells together and trigger tumor-cell destruction•NKCEs can show killing potency superior to therapeutic Abs in vitro and in vivo•NKCEs may improve benefit-risk profile for cancer treatment compared to BiTEs Trifunctional antibodies that engage natural killer cells by binding NKp46 and CD16, in addition to an antigen on cancer cells, show higher potency than current clinically available therapeutic antibodies.