IND-enabling development for IN-002, an inhaled muco-trapping mAb against respiratory syncytial virus

Project Summary Respiratory Syncytial Virus (RSV) is the leading cause of viral death in infants and young children, and is also a major cause of respiratory illness in immune compromised adults and the elderly. Unfortunately, there is currently no vaccine or effective therapy available for RSV. Synagis, a monthly intramuscular injection of the monoclonal antibody (mAb) palivizumab, is the only FDA-approved intervention, but can only be used for prevention and is given only to a very small subset of high-risk infants. Synagis is not effective at treating RSV after infection has begun. Thus, for the tens of thousands hospitalized with RSV, only supportive therapy is available; the resulting morbidity and mortality are substantial, particularly among the immunocompromised. Interestingly, RSV spreads in the lung via shedding of virus exclusively into the airway; thus, RSV must traverse the airway mucus (AM) before infecting other neighboring cells, and remains restricted to the airways with little-to-no systemic viremia. This unique pathophysiology makes RSV difficult to target by systemically dosed therapies. We believe an RSV-specific, safe and effective antiviral therapy that can be inhaled directly into the respiratory tract would provide a powerful option addressing the current gap in pharmacological interventions. To meet this goal, Inhalon has been advancing IN-002, developed using its proprietary and patented “muco-trapping” mAb technology platform. IN-002 is a potent anti-F mAb with picomolar binding affinity and neutralization potency, has minimal risk of viral escape, and possess suitable Fc N-glycosylation for trapping RSV in AM. In turn, trapped RSV are quickly purged from the airways via natural mucociliary clearance mechanisms. We have further formulated IN-002 to be stably nebulized using a vibrating mesh nebulizer. By concentrating IN-002 directly at the site of infection, rather than delivering the mAb systemically, we expect to enable efficacious and cost-effective treatment of RSV, with little risk of adverse side effects due to limited systemic adsorption from pulmonary delivery. In a neonatal lamb model of RSV infection, daily nebulized therapy with IN-002 initiated even at near peak viral titers in the lung was able to reduce infectious RSV viral load in the lungs and BALF to almost non-detectible levels within 3 days. Inhalon is currently actively engaging in cell line development for IN-002. To enable rapid translation into the clinic, we seek to complete the cell line development in this proposal, and produce tox materials suitable for IND-enabling activities such as Tissue Cross Reactivity studies, GLP pulmonary tox studies, and GLP nebulization characterization studies. Together, the proposed work will support rapid advancement of IN-002 into clinical testing. Our work here with RSV will also help pave the way for improved, molecularly-targeted, inhaled therapies for other respiratory pathogens.