CD3和CD2信号的药理学整合触发CD2花冠的形成,从而增强T细胞活化

Redirecting patient's endogenous T cells to safely and effectively eradicate tumors continues to offer compelling therapeutic opportunities. We found that EVOLVE, a trispecific antibody targeting a tumor-specific antigen together with integrated CD3 activation and CD2 costimulation, led to unique T cell activation profiles. Like the events observed with intact or artificial antigen presenting cells, these trispecific antibodies were sufficient to trigger the formation of a CD2 corolla surrounding the immunological synapse, independent of membrane CD58, on 95% primary human T cells, in a tumor-antigen dependent manner, compared to 20% observed with CD3-matched bispecifics. Trispecific antibodies demonstrated significant functional advantages over conventional bispecific antibodies, with corolla-associated signaling leading to a 1.6-fold amplification of T cell activation events. This resulted in an over 10-fold increase in killing potency against high-antigen-expressing tumor cells and a 20-fold enhancement of killing potency against low-antigen-expressing tumor cells. These findings provide fundamental insights into the CD2 tropism for corolla localization, even when the CD2 and CD3 ligands are covalently linked to each other, confirming the potential for EVOLVE to initiate CD2-costimulatory signaling at the T cell synapse, thereby enhancing the therapeutic efficacy of T cell engagers.