Development of IN-003PI as passive immunization against human metapneumovirus infection

Project Summary Human Metapneumovirus (MPV) is the second leading cause of lower respiratory tract infections (LRTI) in infants and young children, and a major cause of respiratory illness in the immunocompromised and the elderly. Unfortunately, there is currently no effective therapy, prophylaxis, or vaccine available for MPV, and only supportive care is available for those hospitalized with MPV LRTIs. MPV LRTIs can be lethal, with an observed hospital mortality rate among all MPV infections of ~10%, which approximates the ~9% mortality rate for influenza-infected adults admitted to the ICU. MPV shares much of the same pathophysiology as RSV, a closely related respiratory infection. RSV- induced LRTIs in infants can be effectively reduced by passive immunization, as illustrated by the clinical success of Synagis® (palivizumab), a monthly shot given to premature infants during the RSV season for at least 20 years, and the recently approved Beyfortus® (nirsevimab), a one-time shot indicated for all infants entering their first RSV season (not just high-risk infants). The clinical effectiveness of both Synagis® and Beyfortus®, which reduce RSV LRTIs by 70-80%, suggests that passive immunization should help similarly reduce risk for MPV-LRTIs. Inhalon is a clinical stage startup focused on advancing interventions against diverse respiratory infections, including MPV, RSV, SARS-CoV-2, and influenza. We are actively developing IN-003 to address the unmet clinical burden of MPV LRTIs. IN-003 is comprised of a pair of neutralizing mAbs against MPV-F proteins, originally identified from a library of human neutralizing mAbs against MPV, each of which bind and neutralize diverse MPV strains with picomolar affinities. Importantly, both mAbs exhibit strong resistance to viral escape. In this work, we plan to advance IN-003PI (i.e. IN-003 for passive immunization) against MPV LRTIs. We have shown in vivo that the individual IN-003 mAbs offer effective passive immunization against MPV in cotton rats and mice, and also prevent MPV infections ex vivo when dosed basally to well-differentiated human airway epithelial cultures prior to apical inoculation of MPV. To enable once-seasonal protection, the IN-003 mAbs will incorporate LS mutations in the to greatly increase affinity to FcRn and therefore prolong circulation. Herein, we will file a pre-IND meeting with the FDA, produce a GLP tox batch of IN-003PI, and conduct key IND-enabling studies, including GLP tox in non-human primates. The proposed work represents the critical path to advance IN-003PI into the clinic. Successful completion of this work will put us in a position to quickly file IND following production of GMP clinical trial materials for the first clinical study of an immunoprophylaxis against MPV.