A NOVEL TLR7/8 ANTAGONIST BLOCKS PRO-INFLAMMATORY FUNCTION OF IMMUNE COMPLEXES FROM LUPUS PATIENTS AND ABROGATES LUPUS-LIKE DISEASE IN MICE

S. Hawtin, C. André, G. Collignon Zipfel, S. Appenzeller, B. Bannert, L. Baumgartner, D. Beck, C. Betschart, T. Boulay, H. Brunner, M. Ceci, J. Deane, R. Feifel, E. Ferrero, D. Kyburz, F. Lafossas, P. Loetscher, C. Merz-Stoeckle, P. Michellys, B. Nuesslein-Hildesheim, F. Raulf, J. Rush, G. Ruzzante, T. Stein, S. Zaharevitz, G. Wieczorek, R. Siegel, P. Gergely, T. Shisha, T. JuntNovartis Institute of Biomedical Research, Immunology, Basel, Switzerland UNICAMP Universidade Estadual de Campinas, School of Medicine, Orthopedics, Rheumatology and Traumatology, Campinas, Brazil Universitätsspital Basel, Rheumatology, Basel, Switzerland Cincinnati Children’s Hospital Medical Center, Rheumatology, Cincinnati, United States of America Novartis Institute of Biomedical Research, Cancer Research, San Diego, United States of America Novartis Institute of Biomedical Research, Chemistry, San Diego, United States of America Novartis Institute of Biomedical Research, Translational Medicine, Basel, Switzerland  Background Toll-like receptors (TLR) 7 and 8 are innate sensors of single stranded RNA (ssRNA). Genetic and in vivo evidence suggests that aberrant recognition of RNA-containing autoantigens by TLR7/8 drives autoimmune diseases (Junt and Barchet, 2015). More validation for a pathogenic effect of TLR7 in chronic inflammation comes from recent data showing that a TLR7 gain-of-function mutation is sufficient to drive lupus-like disease (Brown et al., 2022). Objectives Here we report on the preclinical characterization of MHV370, a highly selective, orally active TLR7/8 inhibitor for treatment of chronic inflammatory diseases. Methods We used a suite of in vitro profiling assays to investigate the effect of MHV370 on TLR responses. This included the stimulation of PBMCs by immune complexes from systemic lupus erythematosus patient sera. Furthermore we characterized MHV370 in different mouse models of acute and chronic TLR7-driven inflammation. Results In vitro, MHV370 interfered with TLR7/8-dependent production of cytokines in humans and mice, most notably of interferon alpha, a clinically validated driver of autoimmune diseases. MHV370 abrogates B cell, monocyte, and neutrophil responses downstream of TLR7/8. In vivo, prophylactic or therapeutic administration of MHV370 suppressed TLR7-dependent cytokines and interferon stimulated genes. In the NZB/W F1 mouse model of lupus, MHV370 prevented halted disease progression and glomerulonephritis. Unlike hydroxychloroquine, MHV370 interfered with cytokine production triggered by immune complexes between systemic lupus erythematosus patient sera and necrotic cell extract, suggesting differentiation from clinical standard of care. Conclusion The pharmacological data presented here support further development of MHV370 towards clinical proof of concept trials in man. References Brown, G.J., Canete, P.F., Wang, H., Medhavy, A., Bones, J., Roco, J.A., He, Y., Qin, Y., Cappello, J., Ellyard, J.I., et al. (2022). TLR7 gain-of-function genetic variation causes human lupus. Nature 605, 349-356. Junt, T., and Barchet, W. (2015). Translating nucleic acid-sensing pathways into therapies. Nature reviews Immunology 15, 529-544. Acknowledgements: NIL. Disclosure of Interests Stuart Hawtin Shareholder of: Novartis, Employee of: Novartis, Cédric André Shareholder of: Novartis, Employee of: Novartis, Géraldine Collignon Zipfel Shareholder of: Novartis, Employee of: Novartis, Simone Appenzeller: None declared, Bettina Bannert: None declared, Lea Baumgartner Shareholder of: Novartis, Employee of: Novartis, Damian Beck Shareholder of: Novartis, Employee of: Novartis, Claudia Betschart Shareholder of: Novartis, Employee of: Novartis, Thomas Boulay Shareholder of: Novartis, Employee of: Novartis, Hermine Brunner Speakers bureau: Novartis, Pfizer, Roche, Grant/research support from: From Pfizer. The Cincinnati Children’s Hospital where Dr. Brunner works as a full-time employee, has received contributions from the following industries in the past 2 years: AbbVie, Astra Zeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Celgene, Cerocor, horizon, Janssen, Eli Lilly, Idorsia, Cerocor, F. Hoffmann-La Roche, Merck, Novartis, and Sanofi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment to third parties, Melanie Ceci Shareholder of: Novartis, Employee of: Novartis, Jonathan Deane Shareholder of: Novartis, Employee of: Novartis, Kumquat Biosciences, Roland Feifel Shareholder of: Novartis, Employee of: Novartis, Enrico Ferrero Shareholder of: Novartis, Employee of: Novartis, GSK, Diego Kyburz Consultant of: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, Roche, Grant/research support from: Abbvie, Frederique Lafossas Shareholder of: Novartis, Employee of: Novartis, Pius Loetscher Shareholder of: Novartis, Employee of: Novartis, Christina Merz-Stoeckle Shareholder of: Novartis, Employee of: Novartis, Pierre Michellys Shareholder of: Novartis, Employee of: Novartis, Odyssey Therapeutics, Barbara Nuesslein-Hildesheim Shareholder of: Novartis, Employee of: Novartis, Friedrich Raulf Shareholder of: Novartis, Employee of: Novartis, James Rush Shareholder of: Novartis, Employee of: Novartis, Kling Bio, Giulia Ruzzante Shareholder of: Novartis, Employee of: Novartis, Thomas Stein Shareholder of: Novartis, Employee of: Novartis, Samantha Zaharevitz Shareholder of: Novartis, Employee of: Novartis, Grazyna Wieczorek Shareholder of: Novartis, Employee of: Novartis, Richard Siegel Shareholder of: Novartis, Employee of: Novartis, Peter Gergely Shareholder of: Novartis, Employee of: Novartis, Tamas Shisha Shareholder of: Novartis, Employee of: Novartis, Tobias Junt Shareholder of: Novartis, Employee of: Novartis. Keywords: Innate immunity, Disease-modifying drug (DMARDs), Systemic lupus erythematosus DOI: 10.1136/annrheumdis-2023-eular.1655Citation: , volume 82, supplement 1, year 2023, page 899Session: SLE, Sjön’s and APS - treatment (Poster View)