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

Inhalon Biopharma, Inc., Morrisville NC

Investigators

Abstract

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.