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.
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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 3

PGDM1400 and PGT121 are expressed as dmAbs in NHPs.

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PGDM1400 and PGT121 are expressed as dmAbs in NHPs. Immune-competent mac...
Immune-competent macaques were injected with hIgG1 dmAb constructs (d0) and serially bled. Group 1 animals (n = 4) received 6 mg of PGDM1400-encoding plasmid DNA; group 2 animals (n = 4) received 3 mg of PGDM1400 and 3 mg of PGT121 plasmid DNA. (A) Quantification of hIgG1 in the sera of group 1 and group 2 NHPs over time. (B) Peak expression levels of total hIgG1 for each group at d14. (C) Serum-binding curves against HIV-1 Env trimer, BG505_MD39, using different secondary antibodies to establish the binding of PGDM1400 (hIgG1-κ LC, blue) and PGT121 (hIgG1-λ LC, green). (D) Neutralization IC50 of serum across the 12-virus global pseudotype panel using serum from peak dmAb expression (d14). (E) Baseline subtracted ADCC-killing activity of serum for IMC DU151 compared with recombinant mAbs PGDM1400 and PGT121. Horizontal bars indicate mean; error bars represent SEM. Expression levels and neutralization titers are representative of 2 replications; all other tests were performed once. Two-tailed Student’s t test was performed to determine significant differences in levels of expression between group 1 and group 2. P < 0.05 was considered significant.