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 November 7, 2019
Citation Information: J Clin Invest. 2020;130(2):827-837. https://doi.org/10.1172/JCI132779.
View: Text | PDF
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

×

Figure 2

Delivery of multiple dmAb constructs in a single mouse maintains individual dmAb expression levels and increases serum neutralization breadth.

Options: View larger image (or click on image) Download as PowerPoint
Delivery of multiple dmAb constructs in a single mouse maintains individ...
(A) Groups of mice (n = 5) were administered a single dmAb (PG121, PGT145, PGDM1400, 3BNC117, or 10-1074) or a combination of 2 dmAbs (PGT121+PGT145, PGDM1400+PGT121, 3BNC117+10-1074). Peak serum expression levels of human IgG were quantified by ELISA. (B) Mean (n = 5) IC50 pseudotype neutralization against the 12 viruses of the global panel and MLV control of sera collected at d14 from mice administered a single or 2 dmAbs. 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. (C) Total human IgG serum expression levels following administration of individual dmAbs (PGDM1400, PGT151, VRC01, and PGT121) and coadministration of all 4 dmAbs (combo) in mice (n = 5). (D) Mean (n = 5) IC50 pseudotype neutralization against the 12 viruses of the global panel and MLV for sera collected from mice administered individual dmAbs and combination of the 4 dmAbs. Horizontal bars indicate mean; error bars represent SEM. Expression levels are representative of 2 experimental replicates; binding and neutralization testing were performed once.