Research Project
10157638
Project Summary Respiratory syncytial virus (RSV) and metapneumovirus (MPV) are the two leading viral causes of death in infants and young children, and are major causes of respiratory illness in immunocompromised adults and the elderly. Unfortunately, there is currently no vaccine or effective therapy available for either infection. Synagis, a monthly intramuscular injection of the monoclonal antibody (mAb) palivizumab, is the only FDA-approved intervention given to a very small subset of high-risk infants as immunoprophylaxis. However, it is not effective at treating RSV infections. There are no MPV treatments currently in any stage of clinical development. Thus, for the tens of thousands of patients hospitalized for either RSV or MPV, only supportive therapy is available, and morbidity and mortality are substantial. Interestingly, both viruses spread in the lung by shedding daughter viruses exclusively into the airway lumen; shed viruses must then traverse airway mucus (AM) before infecting neighboring cells, and infections remain primarily restricted to the airways with little to no systemic viremia. We believe a virus-specific, safe, effective and topically-delivered antiviral would provide a powerful option to address the current gap in pharmacological interventions. Mucommune is developing MM004 to meet the urgent need for a bronchiolitis treatment, based on our ?muco-trapping? mAb platform. MM-004 is a topical mAb treatment based on (i) bispecific mAb possessing ?muco-trapping? Fc and binding domains that neutralizes both RSV and MPV, and (ii) direct delivery to the lung airways using a vibrating mesh nebulizer. By concentrating MM004 at the site of infection rather than delivering it systemically, we expect to enable efficacious and cost-effective treatment for both RSV and MPV, with little risk of adverse side effects, due to limited systemic adsorption after pulmonary delivery. In RSV-infected neonatal lambs, a highly relevant model for pediatric RSV, our muco-trapping mAb against RSV greatly reduced infectious RSV viral load in infected neonatal lambs in lung tissues to non-detectible levels, and reduced bronchiolitis, neutrophil infiltration and inflammation to levels that were often indistinguishable compared to uninfected animals. Building off this promising result, we have now engineered a bispecific mAb (MM-004) that potently traps both RSV and MPV in human AM and facilitates rapid clearance from the mouse lung. In this proposal, we seek to validate in Phase 1 whether MM004 can effectively treat MPV infections in hamsters, the best available model for MPV. If successful, we will advance to Phase 2, where we will develop a Master Cell Bank cell line for high yield production of MM-004 (Aim 1), and conduct a number of IND-enabling studies including, GLP tox studies in rats, tissue cross reactivity studies, and pre-IND filing (Aim 2). Both Phase 2 Aims are part of the critical path to quickly advance MM-004 into clinical development, and will put us in a position to file IND within 12 months from completing this project. Our work will also help pave the way for improved, molecularly-targeted aerosolized therapies against various respiratory infections.
