Background: Respiratory Syncyctial Virus (RSV) remains the major viral cause of severe lower respiratory tract disease in young infants and children worldwide occurring in annual winter epidemics. A role for antibodies in both the prevention and treatment of RSV infection is strongly supported by studies with murine monoclonal antibodies (MAbs) in animal models and recent clinical results with human intravenous immunoglobulins (IVIG) selected for high anti-RSV neutralizing titers. With their higher potency, Mabs potentially offer distinct advantages over gamma-globulin preparations including lower dose requirements and ease of administration. We are developing a reshaped human (humanized) monoclonal antibody, RSHZ19, which is specific for the fusion (F) protein of RSV and has been genetically engineered to retain the potent anti-RSV activity of its parent murine Mab while minimizing the potential for immunogenicity and short half-life associated with administration of murine Mabs to humans.Objectives: Our preclinical evaluation of RSHZ19 was aimed at demonstrating both safety and efficacy of RSHZ19 against both subtypes (A and B) of RSV and to provide a clear rationale for dose selection prior to testing in humans.Results: The humanized Mab demonstrated equivalent binding to RSV as its parent Mab and was as effective in neutralizing the virus and inhibiting cell fusion in vitro. Importantly, RSHZ19 also recognized all (> 50) clinical isolates tested to date and showed potent neutralizing activity (EC 5 0 s of 0.4-3.0 μg/ml) against a panel of different subtype A and B strains suggesting that its epitope on the F protein is well conserved. RSHZ19 was able to both prevent and treat RSV infection in murine and cotton rat models of RSV infection and reduced the observed histopathology in the lungs of cotton rats at days 4 and 7 post-infection in a dose-related fashion with no evidence for exacerbation of disease that has been observed with some attempts to induce active immunity to RSV. In safety assessment studies, RSHZ19 did not cross-react with human tissue and showed no acute or chronic toxicity in non-human primates with single i.v. doses up to 200 mg/kg and repeat doses up to 40 mg/kg. The clinical potential of RSHZ19 was further emphasized by its long terminal half-life (around 24 days) in cynomolgus macaques and infant baboons and by comparative studies in the cotton rat where RSHZ19 was at least 100-fold more potent than previously described IVIG preparations.Conclusion: Based on these encouraging preclinical results, RSHZ19 was recently safely administered to a group of human adult volunteers. Both the preclinical and early clinical data strongly support the continued development of RSHZ19 in the prevention and treatment of severe RSV-induced disease in humans.