Development of a potent monoclonal antibody for treatment of human metapneumovirus infections

Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for treatment and prevention. We describe the discovery and characterization of 4F11, a highly potent neutralizing mAb with in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we define a unique mechanism of binding employed by 4F11. 4F11 targets an epitope located at the apex of the prefusion F protein (site Ø) with a 1:1 stoichiometry of Fab to trimer, distinct from the 3:1 stoichiometry observed with other HMPV site Ø antibodies. Unlike other site Ø antibodies which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan. In vitro, 4F11 displays high neutralization potency across diverse HMPV strains. It also shows low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation have significantly decreased fitness in vitro. In male hamsters, 4F11 significantly reduces viral loads in the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development.