Nature Major findings: lower affinity agonist antibody is more effective

For a long time, researchers have used high affinity as a key criterion for screening therapeutic antibodies. At present, most of the agonist antibodies in the study have high affinity and activate immune cells by cross-linking the Fc function of the antibody, but these antibodies have little clinical effect or have strong adverse immune reactions.

Recently, the journal Nature published an article entitled "Reducing affinity as a strategy to boost immuomodulatory antibodyism". Different from previous studies, this study proved that unlike traditional antibodies, agonist antibodies do not need to have high affinity, and the relationship between their affinity and agonistic activity is "bell shaped". Within a certain range, with the decrease of affinity, the agonistic ability of antibodies increases, but when the affinity is further reduced, the agonistic activity of antibodies decreases. In the mouse tumor animal model, the low affinity antibody has better therapeutic effect than the high affinity antibody. It is worth noting that the surviving mice can still completely resist tumor after being inoculated with tumor again, which shows that the treatment of low affinity antibody can produce memory immune cells in mice, thus protecting mice from tumor damage for a long time.

The expression level of cell activation markers CD23 (above) and CD86 (below) (mean fluorescence intensity MFI) and antibody affinity (KD value) showed a "bell" relationship

Molecular mechanism research found that the antibody with medium affinity can better mediate the aggregation of receptors. Further studies have shown that antibody mediated receptor aggregation requires bivalent antibodies, and this aggregation is more on the interface between cells.

Confocal microscope observation showed that there was a "bell" relationship between receptor aggregation index and antibody affinity