抗体結合メカニズムの新しい洞察

タイトル: Analysis of emergent bivalent antibody binding identifies the molecular reach as a critical determinant of SARS-CoV-2 neutralisation potency

概要: Key functions of antibodies, such as viral neutralisation, depend on bivalent binding but the factors that influence it remain poorly characterised. Here, we develop and employ a new bivalent model to mechanistically analyse binding between >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces. Our method reproduces the monovalent on/off-rates and enables measurements of the bivalent on-rate and the molecular reach: the maximum antigen separation that supports bivalent binding. We find large variations in these parameters across antibodies, including variations in reach (22-46 nm) that exceed the physical antibody size ([~]15 nm) due to the antigen size. The bivalent model integrates all parameters, including reach and antigen density, to predict an emergent binding potency for each antibody that matches their neutralisation potency. Indeed, antibodies with similar monovalent affinities to the same RBD-epitope but with different reaches display differences in emergent bivalent binding that match differences in their neutralisation potency. Together, our work highlights that antibodies within an isotype class binding the same antigen can display differences in molecular reach that can substantially modulate their emergent binding and functional properties. Lay SummaryAntibodies are soluble proteins that can neutralise pathogens by sticking to them. They contain two identical arms that allow them to simultaneously bind two identical antigen molecules on pathogen surfaces. Although we know that bivalent binding is important for neutralisation, we dont know how different antibodies achieve it. We developed a new model to analyse the mechanism of bivalent binding and used it to study over 45 antibodies from COVID-19 patients that bind the RBD antigen of SARS-CoV-2. Unexpectedly, we found that the molecular reach of an antibody, which is the maximum antigen separation that supports bivalent binding, varied widely between antibodies and exceeded their physical size. We show how antibody binding emerges from the interplay of multiple factors, including reach, and that this emergent binding predicts their neutralisation function. The ability to analyse and predict bivalent binding should improve our understanding and exploitation of antibodies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/556503v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): [email protected]@fc7feborg.highwire.dtl.DTLVardef@1325847org.highwire.dtl.DTLVardef@41ad51_HPS_FORMAT_FIGEXP M_FIG C_FIG