Costimulatory capacity of CD137 mAbs on T cells depends on elaborate CRD structures but not on blocking ligand‒receptor binding

Abstract

AbstractCD137 is mainly a costimulatory receptor of CD8+ T cells. Two representative CD137 antibodies, utomilumab, and urelumab, show different costimulatory capacities in clinical trials. Balancing the antitumor effect and systemic toxicity of T cells activated by CD137 signaling is a challenge that requires clinical consideration. In this study, a panel of specific anti‐human CD137 monoclonal antibodies (mAbs) were prepared and their affinities, isotypes, CD137‐CRD (cysteine‐rich domain) binding regions, cross‐reactivity to mouse and rhesus CD137, inhibition of ligand‒receptor binding and costimulatory activities were analyzed. The results showed that anti‐human CD137 mAbs had high cross‐reactivity with rhesus CD137. MAbs fell into three clusters according to their different binding regions of the CD137 extracellular domain. They bound to CRDI+CRDII, CRDIII or CRDIV+STP. CRDIII‐binding mAbs had the strongest blocking activity. Highly costimulatory CD137 mAbs showed stronger abilities to promote CD8+ T‐cell proliferation. However, the costimulatory capacity of mAbs on T cells was not closely related to their ability to block CD137L‐CD137 binding and may be controlled by more elaborate CRD conformational structures. This study provides additional information for the development of next‐generation CD137 mAbs to meet clinical needs.