title: 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-1of mRNA into mice results in ∼170 μg ml-1VRC01 antibody concentrations in the plasma 24 h post injection. Weekly injections of 1 mg kg-1of 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.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Norbert
authors.initials: N
authors.lastname: Pardi
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Secreto
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Shan
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Fotini
authors.initials: F
authors.lastname: Debonera
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Glover
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Yi
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Muramatsu
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Houping
authors.initials: H
authors.lastname: Ni
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Mui
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Ying K
authors.initials: YK
authors.lastname: Tam
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Farida
authors.initials: F
authors.lastname: Shaheen
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Karikó
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Danet-Desnoyers
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Madden
authors.affiliation: Acuitas Therapeutics, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hope
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Drew
authors.initials: D
authors.lastname: Weissman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics; D057134:Antibodies, Neutralizing / Q000235:genetics*; D000080908:Broadly Neutralizing Antibodies; D004334:Drug Administration Schedule; D005260:Female; D015483:HIV Antibodies / Q000096:biosynthesis; D015658:HIV Infections / Q000276:immunology / Q000628:therapy; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007116:Immunization, Passive; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000737:chemistry; D009705:Nucleosides / Q000737:chemistry*; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies; D008055:Lipids; D009705:Nucleosides; D012333:RNA, Messenger; C578595:VRC01 monoclonal antibody