Production of a human neutralizing monoclonal antibody and its crystal structure in complex with ectodomain 3 of the interleukin-13 receptor α1

摘要

pGene deletion studies in mice have revealed critical roles for IL (interleukin)-4 and -13 in asthma development, with the latter controlling lung airways resistance and mucus secretion. We have now developed human neutralizing monoclonal antibodies against human IL-13Rα1 (IL-13 receptor α1) subunit that prevent activation of the receptor complex by both IL-4 and IL-13. We describe the crystal structures of the Fab fragment of antibody 10G5H6 alone and in complex with D3 (ectodomain 3) of IL-13Rα1. Although the structure showed significant domain swapping within a D3 dimer, we showed that Argsup230/sup, Phesup233/sup, Tyrsup250/sup, Glnsup252/sup and Leusup293/sup in each D3 monomer and Sersup32/sup, Asnsup102/sup and Trpsup103/sup in 10G5H6 Fab are the key interacting residues at the interface of the 10G5H6 Fab–D3 complex. One of the most striking contacts is the insertion of the ligand-contacting residue Leusup293/sup of D3 into a deep pocket on the surface of 10G5H6 Fab, and this appears to be a central determinant of the high binding affinity and neutralizing activity of the antibody./p