RECOMBINANT HUMAN RESPIRATORY SYNCYTIAL VIRUS (RSV) MONOCLONAL-ANTIBODY FAB IS EFFECTIVE THERAPEUTICALLY WHEN INTRODUCED DIRECTLY INTO THE LUNGS OF RSV-INFECTED MICE

Previously, recombinant human respiratory syncytial virus (RSV) monocl onal antibody Fabs were generated by antigen selection from random com binatorial libraries displayed at the tip of filamentous phage. Two su ch Fabs, which exhibited high binding affinity for RSV F glycoprotein (a major protective antigen), were evaluated for therapeutic efficacy in infected mice just before or at the time of peak virus replication in the lungs. Fab 19, which neutralized RSV infectivity with high effi ciency in tissue culture, was effective therapeutically when delivered directly into the lungs by intranasal instillation under anesthesia. In contrast, RSV Fab 126, which failed to neutralize virus in cell cul ture, did not exhibit a therapeutic effect 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 rather small. In four se parate experiments, a single instillation of 12.9-50 mu g of RSV Fab 1 9 was sufficient to achieve such a reduction in pulmonary virus in a 2 5g mouse. The use of Fabs instead of the whole immunoglobulin molecule s from which they are derived reduced the protein content of a therape utic dose. This is important because the protein load that can be deli vered effectively into the lungs is limited. The therapeutic effect of a single treatment with Fab 19 was not sustained, so that a rebound i n pulmonary virus titer occurred on the 2nd day after treatment. This rebound in pulmonary RSV titer could be prevented by treating infected mice with a single dose of Fab 19 daily for 3 days. These observation s suggest that human monoclonal Fabs grown in Escherichia coil may pro ve useful in the treatment of serious RSV disease as well as diseases caused by other viruses where replication in vivo is limited primarily to the lumenal lining of the respiratory tract.