In vivo delivery of synthetic DNA-encoded antibodies induces broad HIV-1-neutralizing activity.

Autor:	Wise MC; Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA., Xu Z; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Tello-Ruiz E; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA., Beck C; Duke Human Vaccine Institute and., Trautz A; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA., Patel A; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA., Elliott ST; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA., Chokkalingam N; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA., Kim S; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA., Kerkau MG; Duke Human Vaccine Institute and., Muthumani K; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA., Jiang J; Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA., Fisher PD; Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA., Ramos SJ; Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA., Smith TR; Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA., Mendoza J; Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA., Broderick KE; Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA., Montefiori DC; Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA., Ferrari G; Duke Human Vaccine Institute and., Kulp DW; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA., Humeau LM; Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA., Weiner DB; Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2020 Feb 03; Vol. 130 (2), pp. 827-837.
DOI:	10.1172/JCI132779
Abstrakt:	Interventions to prevent HIV-1 infection and alternative tools in HIV cure therapy remain pressing goals. Recently, numerous broadly neutralizing HIV-1 monoclonal antibodies (bNAbs) have been developed that possess the characteristics necessary for potential prophylactic or therapeutic approaches. However, formulation complexities, especially for multiantibody deliveries, long infusion times, and production issues could limit the use of these bNAbs when deployed, globally affecting their potential application. Here, we describe an approach utilizing synthetic DNA-encoded monoclonal antibodies (dmAbs) for direct in vivo production of prespecified neutralizing activity. We designed 16 different bNAbs as dmAb cassettes and studied their activity in small and large animals. Sera from animals administered dmAbs neutralized multiple HIV-1 isolates with activity similar to that of their parental recombinant mAbs. Delivery of multiple dmAbs to a single animal led to increased neutralization breadth. Two dmAbs, PGDM1400 and PGT121, were advanced into nonhuman primates for study. High peak-circulating levels (between 6 and 34 μg/ml) of these dmAbs were measured, and the sera of all animals displayed broad neutralizing activity. The dmAb approach provides an important local delivery platform for the in vivo generation of HIV-1 bNAbs and for other infectious disease antibodies.
Databáze:	MEDLINE
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