Characterization of a human-mouse chimeric monoclonal antibody targeting
rabies virus glycoprotein
Abstract
At present, the horse or human rabies immunoglobulin (RIG) used for
post-exposure prevention of human rabies (PEP) has high cost and limited
availability. It is strongly encouraged to replace RIG with equivalent
or more effective and safer products. Mouse and human monoclonal
antibodies have been shown to protect rodents from lethal rabies virus
(RABV) attacks. In this study, we reported a human-mouse chimeric
monoclonal antibody, 12-2A12, which showed a strong neutralization
potency and a wide breadth against multiple street viruses of RABV in
vitro. The antibody binds the viral glycoprotein (G) with nanomolar
affinity. The complex structure of 12-2A12 bound to RABV G reveals that
the antibody recognizes an epitope that partially overlaps with the
recognition region for the nicotinic acetylcholine receptor (nAChR). The
antibody therefore would interfere with the nAChR/G interaction to block
the viral receptor binding. In addition, comparison of our complex
structure with the G structure in the acidic state reveals a clear
steric clash, highlighting that the antibody would further prevent the
conformational changes of the viral glycoprotein that are essential for
membrane fusion. In light of these functional and structural data, we
believe that 12-2A12 might be developed to be included in an antibody
cocktail for potential use in human rabies PEP.