J Virol . Airway Delivery of Anti-influenza Monoclonal Antibodies Results in Enhanced Anti-Viral Activities and Enables Broad Coverage Combination Therapies

[tetano]

J Virol


. 2020 Aug 26;JVI.00052-20.
doi: 10.1128/JVI.00052-20. Online ahead of print.
Airway Delivery of Anti-influenza Monoclonal Antibodies Results in Enhanced Anti-Viral Activities and Enables Broad Coverage Combination Therapies


Adam Vigil ¹ , Natalia Frias-Staheli ¹ , Teresa Carabeo ¹ , Michael Wittekind ²



Affiliations

• PMID: 32847855
• DOI: 10.1128/JVI.00052-20

Free article

Abstract

Effective and reliable anti-influenza treatments are acutely needed and passive-immunizations using broadly neutralizing anti-influenza monoclonal antibodies (bnAbs) are a promising emerging approach. Because influenza infections are initiated in and localized to the pulmonary tract, and newly formed viral particles egress from the apical side of the lung epithelium, we compared the effectiveness of hemagglutinin (HA) stalk-binding bnAbs administered through the airway (intranasal or via nebulization) versus the systemic route (intra-peritoneal or intravenous). Airway deliveries of various bnAbs were 10- to 50-fold more effective than systemic deliveries of the same bnAbs in treating H1N1, H3N2, B/Victoria-, and B/Yamagata-lineage influenza viral infections in mouse models. The potency of airway-delivered anti-HA bnAbs were highly dependent on anti-viral neutralization activity with little dependence on the effector function of the antibody. In contrast, effectiveness of systemically-delivered anti-HA bnAbs were not dependent on anti-viral neutralization, but critically dependent on antibody effector functions. Concurrent administration of a neutralizing/effector function-positive bnAb via the airway and systemic routes showed increased effectiveness. The low amount of airway-delivered bnAbs needed for effective influenza treatment create the opportunity to combine potent bnAbs with different anti-influenza specificities to generate a cost-effective antiviral therapy that provides broad coverage against all circulating influenza strains infecting humans. A 3 mg/kg dose of the novel triple antibody combination CF-404 (i.e. 1 mg/kg of each component bnAb) delivered to the airway was shown to effectively prevent weight-loss and death in mice challenged with ten LD₅₀ inoculums of either H1N1, H3N2, B/Victoria-lineage, or B/Yamagata-lineage influenza viruses.IMPORTANCE Influenza causes widespread illness in humans and can result in morbidity and death, especially in the very young and elderly populations. Because influenza vaccination can be poorly effective some years, and the immune system of the most susceptible populations are often compromised, passive immunization treatments using broadly-neutralizing antibodies is a promising therapeutic approach. However, large amounts of a single antibody are required for effectiveness when delivered through systemic administration (typically intravenous infusion) precluding the feasible dosing of antibody combinations via this route. The significance of our research is the demonstration that effective therapeutic treatments of multiple relevant influenza types (H1N1, H3N2, and B) can be achieved by airway administration of a single combination of relatively small amounts of three anti-influenza antibodies. This advance exploits the discovery that airway delivery is a more potent way of administering anti-influenza antibodies compared to systemic delivery, making this a feasible and cost-effective therapeutic approach.