In vivo delivery of synthetic DNA–encoded antibodies induces broad HIV-1–neutralizing activity
Megan C. Wise, … , Laurent M. Humeau, David B. Weiner
Megan C. Wise, … , Laurent M. Humeau, David B. Weiner
Published January 6, 2020; First published November 7, 2019
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI132779.
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Research Article AIDS/HIV Immunology

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

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 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.

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 D. Fisher, Stephany J. Ramos, Trevor R.F. Smith, Janess Mendoza, Kate E. Broderick, David C. Montefiori, Guido Ferrari, Daniel W. Kulp, Laurent M. Humeau, David B. Weiner

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Figure 1

In vivo expression of dmAb-encoded HIV-1 bNAbs in mice.

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In vivo expression of dmAb-encoded HIV-1 bNAbs in mice. (A) Peak dmAb e...
(A) Peak dmAb expression levels (d14) of bNAbs in the sera of transiently immunodepleted mice. Groups of mice (n = 5) were administered dmAb constructs expressing 1 of 16 different bNAbs. (B) Binding curves for 4 dmAbs against HIV-1 trimer BG505_MD39. Serum dmAb levels were normalized for expression (colored lines, n = 5 mice) and compared with the similar purified recombinant protein (black lines) over various concentrations. (C) Individual mouse IC50 (n = 5) for 4 dmAbs across the 12 viruses of the global panels (blue circles) versus values reported in the literature (red squares). Literature values gathered from Los Alamos CATNAP. (D) Mean (n = 5) IC50 pseudotype neutralization of d14 mouse sera against the 12 viruses of the global panel and MLV control. Value of 45 corresponds to no neutralization at a 1:45 dilution, the lowest dilution of the mouse serum tested. All other values are in μg/ml. Horizontal bars indicate mean; error bars represent SEM. Expression levels are representative of 2 experimental replicates; binding and neutralization testing were performed once.