Targeted delivery of immune-stimulating bispecific RNA, inducing apoptosis and anti-tumor immunity in cancer cells
Tony Rady,
Stéphane Erb,
Safia Deddouche-Grass,
Renaud Morales,
Guilhem Chaubet,
Sarah Cianférani,
Nicolas Basse,
Alain Wagner
Affiliations
Tony Rady
Bio-Functional Chemistry (UMR 7199), LabEx Medalis, University of Strasbourg, 74 Route du Rhin, 67400 Illkirch-Graffenstaden, France; Sanofi, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France
Stéphane Erb
Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg, CNRS, IPHC UMR 7178, 67000 Strasbourg, France; Infrastructure Nationale de Protéomique ProFI – FR2048, 67087 Strasbourg, France
Safia Deddouche-Grass
Sanofi, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France
Renaud Morales
Sanofi, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France
Guilhem Chaubet
Bio-Functional Chemistry (UMR 7199), LabEx Medalis, University of Strasbourg, 74 Route du Rhin, 67400 Illkirch-Graffenstaden, France
Sarah Cianférani
Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg, CNRS, IPHC UMR 7178, 67000 Strasbourg, France; Infrastructure Nationale de Protéomique ProFI – FR2048, 67087 Strasbourg, France
Summary: Double-stranded RNAs (dsRNA)-based strategies appeared as promising therapies to induce an inflammation in the tumor microenvironment. However, currently described systems generally lack active targeting of tissues, and their clinical translation is thus limited to intratumoral injection. Herein, we developed an antibody-siRNA-5′triphosphate conjugate with multiple modes of action, combining cell surface EphA2-specific internalization, leading to a simultaneous gene silencing and activation of the receptor retinoic acid-inducible gene I (RIG-I). Recognition of cytosolic siRNA-5′triphosphate by RIG-I triggers the expression of interferons and pro-inflammatory cytokines, inducing an inflammation of the tumor environment and activating neighboring immune cells. In addition, these RIG-I-specific effects synergized with siRNA-mediated PLK1 silencing to promote cancer cell death by apoptosis. Altogether, such immune-stimulating antibody-RNA conjugate opens a novel modality to overcome some limitations encountered by dsRNA molecules currently in clinical trials.
