Direct Administration in the Respiratory Tract Improves Efficacy of Broadly Neutralizing Anti-Influenza Virus Monoclonal Antibodies

Abstract

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.

Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor

“…delivery 22 and in a study on an anti-influenza virus neutralizing monoclonal antibody (MAb) that revealed higher concentrations of the antibody in the bronchoalveolar lavage fluid (BAL), with low penetration into the bloodstream upon direct delivery to the respiratory tract. 23 Moreover, local delivery of an anti-VEGF MAb to K-ras-induced adenocarcinoma-bearing lungs efficiently reduced tumor burden at »100-fold lower serum concentration of MAb than that after systemic delivery. 24 To our knowledge, ours is the first study to evaluate this route in administering an antibody to deplete a suppressive immune population.…”

Monoclonal antibody therapy for Junin virus infection

“…Indeed, recent studies have highlighted the potential of mAbs for intervening late in viral disease (26)(27)(28)(29), even under conditions of high viral load. mAbs are generally more potent than broad-spectrum antivirals, but because of their high specificity, mAbs sacrifice broad-spectrum activity.…”

Two Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Studies To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza A Virus Monoclonal Antibody, MHAA4549A, in Healthy Volunteers

“…The decision to assess high doses in trial 2 was based on the hypothesis that severely ill patients hospitalized with influenza virus infection have higher viral loads and longer durations of viral shedding (15). These patients may require higher doses of MHAA4549A to achieve sufficient occupancy of virus binding sites in the upper and lower respiratory compartments, and a high concentration of IgG would be necessary in the circulating plasma to enable passive transudation into the site of action for influenza virus, the respiratory mucosa (16,17). The initial dose selection for trial 2 was based on an exploratory exposure-response analysis of a phase 2a influenza virus challenge study in healthy volunteers (clinical trial NCT01980966), which indicated that higher MHAA4549A nasal exposure was associated with better efficacy.…”