Recombinant human respiratory syncytial virus (RSV) monoclonal antibody Fab is effective therapeutically when introduced directly into the lungs of RSV-infected mice.

摘要

Previously, recombinant human respiratorysyncytial virus (RSV) monoclonal antibody Fabs were generated by antigenselection from random combinatorial libraries displayed at the tip offilamentous phage. Two such Fabs, which exhibited high binding affinity for RSVF glycoprotein (a major protective antigen), were evaluated for therapeuticefficacy in infected mice just before or at the time of peak virus replicationin the lungs. Fab 19, which neutralized RSV infectivity with high efficiency intissue culture, was effective therapeutically when delivered directly into thelungs by intranasal instillation under anesthesia. In contrast, RSV Fab 126,which failed to neutralize virus in cell culture, did not exhibit a therapeuticeffect under these conditions. The amount of Fab 19 required to effect a 5000-to 12,000-fold reduction in titer of RSV in the lungs within 24 hr was rathersmall. In four separate experiments, a single instillation of 12.9-50 microgramsof RSV Fab 19 was sufficient to achieve such a reduction in pulmonary virus in a25g mouse. The use of Fabs instead of the whole immunoglobulin molecules fromwhich they are derived reduced the protein content of a therapeutic dose. Thisis important because the protein load that can be delivered effectively into thelungs is limited. The therapeutic effect of a single treatment with Fab 19 wasnot sustained, so that a rebound in pulmonary virus titer occurred on the 2ndday after treatment. This rebound in pulmonary RSV titer could be prevented bytreating infected mice with a single dose of Fab 19 daily for 3 days. Theseobservations suggest that human monoclonal Fabs grown in Escherichia coli mayprove useful in the treatment of serious RSV disease as well as diseases causedby other viruses where replication in vivo is limited primarily to the lumenallining of the respiratory tract.