Journal Article

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

Hope, Michael J., Mui, Barbara L., Secreto, Anthony J., Karikó, Katalin, Shan, Xiaochuan, Collman, Ronald G., Muramatsu, Hiromi, Pardi, Norbert, Weissman, Drew, Shaheen, Farida, Glover, Joshua, Tam, Ying K., Danet-Desnoyers, Gwenn A., Madden, Thomas D., Ni, Houping, Debonera, Fotini, Yi, Yanjie

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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 / Immunotherapy / Injection / 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)