Most anti-PD1/PD-L1 antibodies have exhibited poor efficacy in some clinical indications, primarily due to insufficient infiltration of immune cells into the tumor microenvironment (TME). This study presents a novel biological mechanism for the design of an Fc-silenced anti-PD-L1/OX40 bispecific antibody (EMB-09), which aims to augment both peripheral and tumor-associated immune responses, thereby enhancing anti-tumor immunity. Through these mechanisms, EMB-09 has demonstrated superior anti-tumor activity compared to anti-PD-L1 monotherapy in preclinical animal models and has shown preliminary efficacy in early-phase clinical trials. The findings from this study could provide significant insights into cancer immunotherapy by modulating peripheral immune responses beyond the tumor microenvironment.

T cells in the tumor microenvironment require peptide-MHC–T Cell Receptor interaction (Signal 1) coupled with costimulatory receptor engagement (Signal 2) for optimal activation. Because tumors often lack natural costimulatory ligands, a tumor-specific Signal 1 in the absence of Signal 2 may be ineffective or even induce T cell...

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