RESEARCH HIGHLIGHT 08 February 2023

High-affinity binding to target antigens is crucial for the activity of naturally occurring and conventional therapeutic antibodies. In contrast, the impact of affinity on the activity of immunomodulatory antibodies, which modulate receptor signalling, has not been well-studied. To investigate this, Yu et al. generated agonist antibody variants targeting three immunologically important receptors: the stimulatory receptors CD40 and 4-1BB, and the inhibitory receptor PD1. In vitro, low-affinity anti-CD40 monoclonal antibodies exerted augmented agonism and higher immune cell activation, compared with higher-affinity parent molecules. In mice, these low-affinity antibodies induced significantly higher levels of antigen-specific CD8 T cell expansion compared to the parental monoclonal antibody, leading to more potent antitumour activity in a lymphoma model. Similarly, in vitro, lowering the affinity of the inert anti-4-1BB monoclonal antibody utomilumab led to strong 4-1BB-mediated NF-κB activation, while reducing the affinity of the antagonistic anti-PD1 monoclonal antibody nivolumab converted it to an agonist, enhancing PD1 signalling and T cell suppression. Mechanistically, the increased agonistic activity of the low-affinity antibodies was driven by increased receptor clustering.

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doi: https://doi.org/10.1038/d41573-023-00023-x

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