Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge

• Published in: Nature communications Vol. 8; no. 1; pp. 14630 - 8
• Main Authors: Pardi, Norbert, Secreto, Anthony J., Shan, Xiaochuan, Debonera, Fotini, Glover, Joshua, Yi, Yanjie, Muramatsu, Hiromi, Ni, Houping, Mui, Barbara L., Tam, Ying K., Shaheen, Farida, Collman, Ronald G., Karikó, Katalin, Danet-Desnoyers, Gwenn A., Madden, Thomas D., Hope, Michael J., Weissman, Drew
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.03.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/21; 59/5; 631/154/152; 631/61/391; 631/61/51/1568; Animals; Antibodies, Monoclonal - genetics; Antibodies, Neutralizing - genetics; Broadly Neutralizing Antibodies; Drug Administration Schedule; Female; HIV Antibodies - biosynthesis; HIV Infections - immunology; HIV Infections - therapy; HIV-1 - drug effects; HIV-1 - immunology; Humanities and Social Sciences; Humans; Immunization, Passive; Injections; Lipids - chemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Monoclonal antibodies; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Nucleosides - chemistry; Proteins; RNA, Messenger - administration & dosage; RNA, Messenger - chemistry; RNA, Messenger - pharmacology; RNA, Messenger - therapeutic use; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14630

Monoclonal antibodies are one of the fastest growing classes of pharmaceutical products, however, their potential is limited by the high cost of development and manufacturing. Here we present a safe and cost-effective platform for in vivo expression of therapeutic antibodies using nucleoside-modified mRNA. To demonstrate feasibility and protective efficacy, nucleoside-modified mRNAs encoding the light and heavy chains of the broadly neutralizing anti-HIV-1 antibody VRC01 are generated and encapsulated into lipid nanoparticles. Systemic administration of 1.4 mg kg −1 of mRNA into mice results in ∼170 μg ml −1 VRC01 antibody concentrations in the plasma 24 h post injection. Weekly injections of 1 mg kg −1 of mRNA into immunodeficient mice maintain trough VRC01 levels above 40 μg ml −1 . Most importantly, the translated antibody from a single injection of VRC01 mRNA protects humanized mice from intravenous HIV-1 challenge, demonstrating that nucleoside-modified mRNA represents a viable delivery platform for passive immunotherapy against HIV-1 with expansion to a variety of diseases. Monoclonal antibodies are highly effective therapeutics that can be delivered as proteins or encoded DNA or mRNA. Here the authors develop lipid nanoparticle-formulated nucleoside-modified mRNA encoding an HIV-1 neutralizing antibody and see sustained and protective antibody levels in treated mice.