A Recombinant Human Monoclonal Antibody to Human Metapneumovirus Fusion Protein that Neutralizes Virus in Vitro and is Effective Therapeutically in Vivo.
Journal of virology 2007 May 23; 81(15):8315-24
Williams J JV, Chen Z Z, Cseke G G, Wright D DW, Keefer C CJ, Tollefson S SJ,
Departments of Pediatrics, Chemistry, Microbiology and Immunology, and Biostatistics, Vanderbilt Uni
Human metapneumovirus(hMPV) is a recently discovered paramyxovirus that is a major cause of lower respiratory tract disease. hMPV is associated with more severe disease in infants and persons with underlying medical conditions. Animal studies have shown that the hMPV fusion(F) protein alone is capable of inducing protective immunity. Here, we report the use of phage display technology to generate a fully human monoclonal antibody fragment(Fab) with biological activity against hMPV. Phage antibody libraries prepared from human donor tissues were selected against recombinant hMPV F protein with multiple rounds of panning. Recombinant Fabs then were expressed in bacteria, and supernatants were screened by ELISA and immunofluorescent assays. A number of Fabs that bound to hMPV F were isolated, and several of these exhibited neutralizing activity in vitro. Fab DS7 neutralized the parent strain of hMPV with a 60% plaque reduction activity of 1.1 microg/ml and bound to hMPV F with an affinity of 9.8 x10(-10)M as measured by surface plasmon resonance. To test the in vivo activity of Fab DS7, groups of cotton rats were infected with hMPV and administered Fab intranasally three days after infection. Nasal turbinates and lungs were harvested on day four post-infection and virus titers determined. Animals treated with Fab DS7 exhibited a >1500-fold reduction in viral titer in the lungs, with a modest 4-fold reduction in the nasal tissues. There was a dose-response relationship between the dose of DS7 and virus titer. Human Fab DS7 may offer prophylactic or therapeutic potential against severe hMPV infection.