Direct administration in the respiratory tract improves efficacy of broadly neutralizing anti-influenza virus monoclonal antibodies.
The emergence of influenza virus strains resistant to approved neuraminidase inhibitors and the time constrains after infection when these drugs can be effective constitute major drawbacks for this class of drugs. This highlights a critical need to discover new therapeutic agents that can be used for the treatment of influenza virus-infected patients. The use of broadly neutralizing anti-influenza monoclonal antibodies (MAbs) has been sought as an alternative immunotherapy against influenza infection. Here, we tested in mice previously characterized broadly neutralizing anti-hemagglutinin (HA) stalk MAbs prophylactically and therapeutically using different routes of administration. The efficacy of treatment against an influenza H1N1 pandemic virus challenge was compared between two systemic routes of administration, intraperitoneal (i.p.) and intravenous (i.v.), and two local routes, intranasal (i.n.) and aerosol (a.e.). The dose of MAb required for prophylactic protection was reduced by 10-fold in animals treated locally (i.n. or a.e.) compared with those treated systemically (i.p. or i.v.). Improved therapeutic protection was observed in animals treated i.n. on day 5 postinfection (60% survival) compared with those treated via the i.p. route (20% survival). An increase in therapeutic efficacy against other influenza virus subtypes (H5N1) was also observed when a local route of administration was used. Our findings demonstrate that local administration significantly decreases the amount of broadly neutralizing monoclonal antibody required for protection against influenza, which highlights the potential use of MAbs as a therapeutic agent for influenza-associated disease.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Victor H
VH
Leyva-Grado
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Gene S
GS
Tan
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Paul E
PE
Leon
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Mark
M
Yondola
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA peter.palese@mssm.edu.
Peter
P
Palese
D000281:Administration, Intranasal; D061605:Administration, Intravenous; D000336:Aerosols; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D005260:Female; D006388:Hemagglutinins / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects; D007251:Influenza, Human / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D007274:Injections, Intraperitoneal; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D014018:Tissue Distribution
D000336:Aerosols; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; D006388:Hemagglutinins