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

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

Nature Communications, 2017, vol. 8, issue 1, 1-8

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.

Date: 2017
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DOI: 10.1038/ncomms14630

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