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

TLDR

Monoclonal antibodies are a rapidly expanding drug class, but their high development and manufacturing costs limit their potential. The study introduces a safe, cost‑effective platform for in vivo expression of therapeutic antibodies via nucleoside‑modified mRNA. Nucleoside‑modified mRNAs encoding the light and heavy chains of the broadly neutralizing anti‑HIV‑1 antibody VRC01 were generated, encapsulated in lipid nanoparticles, and administered to mice. Systemic delivery of 1.4 mg kg⁻¹ mRNA produced ~170 µg ml⁻¹ VRC01 in plasma after 24 h, weekly 1 mg kg⁻¹ dosing maintained troughs above 40 µg ml⁻¹, and a single injection conferred protection against intravenous HIV‑1 challenge in humanized mice, validating the platform for passive immunotherapy.

Abstract

Abstract 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.