Efficient generation of respiratory syncytial virus (RSV)-neutralizing human MoAbs via human peripheral blood lymphocyte (hu-PBL)-SCID mice and scFv phage display libraries

RSV is one of the major causes of pneumonia and bronchiolitis in infants an d young children and is associated with high mortality. RSV neutralizing hu man antibody (hu-Ab) is known to mediate resistance to viral infection as w ell as to be an effective treatment for severe lower respiratory tract RSV infection. We have previously demonstrated that human primary and secondary immune responses can be established in severe combined immunodeficient mic e engrafted with human peripheral blood lymphocytes (hu-PBL-SCID). By combi ning this animal model with the single-chain Fv antibody (scFv) phage displ ay library technique, we were able to investigate further its clinical pote ntial by generating a panel of human scFvs that exhibit both high F glycopr otein (RSV-F) binding affinities (similar to 10(8) M-1) and strong neutrali zing activities against RSV infection in vitro. Sequencing analysis of the randomly isolated anti-RSV-F scFv clones revealed that they were derived fr om different VH families with mutations in the complementarity-determining region 1 (CDR1). The results suggest that: (i) RSV-F-specific human immune responses and affinity maturation can be induced in hu-PBL-SCID mice; and ( ii) this approach can be applied to generate large numbers of human scFvs w ith therapeutic potential. Despite the fact that hu-PBL-SCID mouse and huma n scFv phage display library have individually been established, our approa ch contributes a simple and significant step toward the generalization of a ntigen-specific human monoclonal antibody (hu-MoAb) production and their cl inical applications.