Mechanistic Studies for the Rational Design of Multivalent Glycodendrimers

We have synthesized B‐antigen‐displaying dendrimers (16‐mers) with different sizes and evaluated their affinity to their IgM antibody in order to investigate which design features lead to effective multivalency. Unexpectedly, the smallest dendrimer, which cannot chelate the multiple binding sites of IgM, clearly exhibited multivalency, together with an affinity similar to or higher than those of the larger dendrimers. These results indicate that the statistical rebinding model, which involves the rapid exchange of clustered glycans, significantly contributes to the multivalency of glycodendrimers. Namely, in the design of glycodendrimers, high‐density glycan presentation to enhance statistical rebinding should be considered in addition to the ability to chelate multiple binding sites. This notion stands in contrast to the currently prevailing scientific consensus, which prioritizes the chelation model. This study thus provides new and important guidelines for molecular design of glycodendrimers. Interaction analysis of B antigen 16‐mers (glycodendrimers), which differ with respect to the length of their linkers, with their IgM antibody revealed that the statistical rebinding model, which involves the rapid exchange of clustered glycans, contributes significantly to the multivalency. These results suggest that in addition to the chelation ability, high‐density glycan‐presentation to enhance statistical rebinding should also be taken into consideration in glycodendrimer design.