RNA-Encoded PGT121-LS Anti-HIV Antibody: Comprehensive Preclinical Characterization and Translational Pharmacokinetics

Tolksdorf, F.; Nelke, J.; Johannson, R.; Caesar, J.; Chaturvedi, A.; Kopp, A.; Fischer, L.; Malz, A.; Kratochvil, S.; Gerhard, I.; Bogen, J. P.; Morin, C.; Kullmann, M.; Seaman, M. S.; Tomaras, G. D.; Yates, N. L.; Ackerman, M. E.; Weiner, J. A.; Ellinghaus, U.; Stadler, C. R.; Sahin, U.; Le Douce, V.

doi:10.64898/2026.06.24.734219

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bioRxiv · 10.64898/2026.06.24.734219

RNA-Encoded PGT121-LS Anti-HIV Antibody: Comprehensive Preclinical Characterization and Translational Pharmacokinetics

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Abstract

Human Immunodeficiency Virus (HIV)-1 broadly neutralizing antibodies (bNAbs) have demonstrated clinical efficacy, but face manufacturing challenges associated with recombinant protein production and purification. Here, we present a ribonucleic acid (RNA)-encoded bNAb (RibobNAb) platform that enables in vivo antibody production of the clinically validated bNAb PGT121 via lipid nanoparticle (LNP) delivery, supporting rapid evaluation of Fc variants (LS, del294, LS-del294) in vitro and in vivo. We confirmed expression, sub-nanomolar HIV-1 Env binding, and potent neutralization across all RibobNAb variants in vitro. In mice, single RNA-LNP administrations yielded in vivo expression of all RibobNAb variants, with PGT121-LS exhibiting a prolonged half-life compared with PGT121. In non-human primates (NHPs), a single intravenous administration of PGT121-LS RNA-LNP was well tolerated without anti-drug antibody (ADA) formation over 180 days and resulted in PGT121-LS half-lives comparable to the reference protein. Single intramuscular administration showed RibobNAb expression but resulted in ADA development from Day 14 onwards and lower bioavailability. In vivo-expressed PGT121-LS RibobNAb retained identical antiviral functionality to PGT121-LS reference protein. An NHP pharmacokinetics model integrating RNA transfection and translation dynamics enabled allometric scaling and first-in-human dose prediction. We highlight RibobNAbs as an alternative to conventional purified protein antibodies for rapid development of bNAb-based therapeutic strategies. O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/734219v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@141319forg.highwire.dtl.DTLVardef@120caadorg.highwire.dtl.DTLVardef@1da2782org.highwire.dtl.DTLVardef@158064d_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

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Tolksdorf, F., Nelke, J., Johannson, R., Caesar, J., Chaturvedi, A., Kopp, A., Fischer, L., Malz, A., Kratochvil, S., Gerhard, I., Bogen, J. P., Morin, C., Kullmann, M., Seaman, M. S., Tomaras, G. D., Yates, N. L., Ackerman, M. E., Weiner, J. A., Ellinghaus, U., Stadler, C. R., Sahin, U., Le Douce, V.. 2026-06-29. RNA-Encoded PGT121-LS Anti-HIV Antibody: Comprehensive Preclinical Characterization and Translational Pharmacokinetics. https://doi.org/10.64898/2026.06.24.734219

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