Project Summary Despite the rollout of vaccines and Paxlovid for SARS-CoV-2, there continues to be significant demand for treatments for COVID-19 that (i) can be easily self-administered at home, (ii) reduce risk of hospitalization, (iii) retain activity against all variants of concern, and (iv) free of drug-drug interactions. SARS-CoV-2, like many common respiratory viruses, spreads in the airways by shedding progeny virions back up into airway mucus (AM) before infecting the next cell. The infection remains almost exclusively restricted to the apical side of the airways as it gradually spreads from the upper respiratory tract to the lower respiratory tract. Importantly, this means that antiviral treatments must reach the airways to have maximal effect. The AM is difficult to reach by systemically dosed antibody-based therapies, since 1% or less of IV-infused mAbs distribute to the AM. Unfortunately, every monoclonal antibody (mAb) for COVID-19 to date has been dosed systemically. Inhalon has pioneered methods for the stable, efficient, inhaled delivery of antibody-based drugs for the treatment of respiratory infections using handheld nebulizers that can administer a dose within minutes per day. Inhalon has also developed a platform of muco-trapping mAbs, based on tuning sugars on the Fc domain of mAbs that enable physical trapping of virions to mucins. Muco-trapping mAbs are unique because they can directly remove the virus from the airways by harnessing natural mucus clearance mechanisms. We validated our inhaled mAb therapy approach in lambs infected with RSV (a virus that also propagates exclusively by apical shedding); when our nebulized treatment was given 3 days post-infection (time of peak viral load), the treated animals benefited from roughly 10,000-fold reductions in viral load, along with excellent improvements in histopathology. Recently, we completed a Phase 1 human clinical study of the safety, tolerability, and pharmacokinetics of another inhaled mAb against SARS-CoV-2, and found excellent safety and high concentrations of drug in the airways, despite using a far lower dose than IV dosing. However, traditional mAbs are always at risk of viral escape by future variants, motivating us to pursue a broad-spectrum solution. Inhalon is advancing IN-007, an inhaled, proprietary, ACE2 decoy-based mAb that retains potent activity against every variant of SARS-CoV-2 (including Omicron BA.4/5). IN-007 is designed to achieve bivalent binding, both intra- and inter- S protein spikes. IN-007 is inherently resistant to viral escape, has much greater binding affinity than conventional ACE2-decoys, enables potent trapping of SARS-CoV-2 in fresh human AM, and was effective in treating SARS-CoV-2 infections in a pilot study in hamsters. By delivering IN- 007 directly to the airways, we expect to enable efficacious and cost-effective treatment for COVID-19, with little risk of adverse side effects. In this project, we seek to produce a GLP batch ...