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

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Abstract

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 which possess the characteristics necessary for potential prophylactic or therapeutic approaches. However, formulation complexities especially for multi-antibody deliveries, long infusion times, and production issues could limit the use of these bNAbs when deployed globally impacting 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 dMAbs cassettes and studied their activity in small and large animals. Sera from animals administered dMAbs neutralized multiple HIV-1 isolates with similar activity to 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 non-human primates for study. High peak circulating levels (between 6-34µg/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.

Authors

Megan C. Wise, Ziyang Xu, Edgar Tello-Ruiz, Charles Beck, Aspen Trautz, Ami Patel, Sarah T.C. Elliott, Neethu Chokkalingam, Sophie Kim, Melissa G. Kerkau, Kar Muthumani, Jingjing Jiang, Paul Fisher, Stephany J. Ramos, Trevor R.F. Smith, Janess Mendoza, Kate E. Broderick, David C. Montefiori, Guido Ferrari, Daniel W. Kulp, Laurent Humeau, David B. Weiner