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

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.

mRNA mediates passive vaccination against infectious agents, toxins, and tumors

“…It conferred full protection against intoxication and virus challenge and could eradicate neoplastic cells in a murine tumor model. While the present manuscript was under review, the feasibility of using mRNA for passive vaccination was independently confirmed in an HIV model (Pardi et al , ).…”

mRNA vaccines — a new era in vaccinology

“…Two early reports demonstrated that dendritic cells (DCs) electroporated with mRNAs encoding antibodies against immuno-inhibitory proteins secreted functional antibodies and improved immune responses in mice 195,196 . Three recent publications have described the use of injectable mRNA for in vivo production of therapeutic antibodies: Pardi and colleagues demonstrated that a single intravenous injection into mice with lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNAs encoding the heavy and light chains of the anti-HIV-1 neutralizing antibody VRC01 rapidly produced high levels of functional antibody in the serum and protected humanized mice from HIV-1 infection 197 ; Stadler and co-workers demonstrated that intravenous administration of low doses of TransIT (Mirus Bio LLC)-complexed, nucleoside-modified mRNAs encoding various anticancer bispecific antibodies resulted in the elimination of large tumours in mouse models 198 ; and Thran and colleagues 199 utilized an unmodified mRNA–LNP delivery system 12 to express three monoclonal antibodies at levels that protected from lethal challenges with rabies virus, botulinum toxin and a B cell lymphoma cell line. No toxic effects were observed in any of these studies.…”

mRNA as novel technology for passive immunotherapy

“…6). While the group of Drew Weissman described successful passive mRNA immunization for prophylaxis of viral infections [267], Stadler et al demonstrated the applicability of mRNA-mediated antibody expression for cancer immunotherapy [264]. The feasibility of using mRNA for such indications was confirmed by Thran et al who applied different mRNAencoded antibody formats to diverse biological threats, viruses, toxins, and tumors [268].…”