Durable suppression of viremia by lipid nanoparticle-formulated RNA encoding for a highly potent HIV-1 neutralizing antibody
Sayettat, S.; Tolksdorf, F.; Johannson, R.; Nelke, J.; Malz, A.; Fischer, L.; Gerhard, I.; Ullrich, N.; Ellinghaus, U.; Stadler, C. R.; Bogen, J. P.; Morin, C.; Knüfer, J.; Stumpf, R.; Schommers, P.; Sahin, U.; Seaman, M. S.; Kratochvil, S.; Klein, F.; Le Douce, V.; Gruell, H.
Show abstract
Recombinant broadly neutralizing antibodies (bNAbs) are promising tools to treat and prevent HIV-1 infection but are associated with manufacturing challenges. To overcome this limitation, we encoded the potent bNAb 1-18-LS on RNA (1-18-LS RibobNAb) for delivery via lipid nanoparticles (LNPs). Indicating high in vivo antibody expression, a 30 ug RNA-LNP intravenous injection resulted in an average peak 1-18-LS RibobNAb serum concentration of 1,061 ug/mL in human neonatal Fc receptor-transgenic mice. Notably, weekly 30 ug RNA-LNP doses maintained higher trough bNAb levels than 500 ug protein injections. Highlighting potent antiviral activity, RNA-LNP-mediated 1-18-LS RibobNAb monotherapy of viremic HIV-1YU2-infected humanized mice resulted in durable HIV-1 suppression without emerging viral escape. Importantly, 1-18-LS RNA-LNP treatment also fully controlled infection after interruption of antiretroviral therapy in humanized mice infected with different patient-derived polyclonal HIV-1 isolates. Our findings provide a proof-of-principle for effective RNA-mediated bNAb immunotherapy of HIV-1 infection.
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