A Novel Designed Anti–PD-L1/OX40 Bispecific Antibody Augments Both Peripheral and Tumor-Associated Immune Responses for Boosting Antitumor Immunity

Bispecific antibodies (BsAb) combining simultaneous PD-L1 blockade and conditional costimulatory receptor activation have been developed to improve immune checkpoint therapy response. However, several PD-L1-based BsAbs have encountered clinical challenges, including insufficient activity or unexpected toxicity. In this study, we propose OX40 as a more suitable target partner for PD-L1-based BsAb design compared with ongoing clinical partners (CD27 and 4-1BB). We present a novel Fc-silenced tetravalent PD-L1/OX40 BsAb (EMB-09), which efficiently blocks PD-1/PD-L1 interactions and induces PD-L1-dependent OX40 activation, leading to enhanced T-cell activation. EMB-09 demonstrated improved antitumor activity compared with the anti-PD-L1 mAb. Significantly, EMB-09 activated effector memory T cells in the peripheral immune system and promoted the influx of stem-like CD8+ T cells into the tumor site, resulting in a more active phenotype of CD8+ tumor-infiltrating lymphocytes. In an ongoing first-in-human study in patients with advanced refractory solid tumors (NCT05263180), EMB-09 demonstrated a consistent pharmacodynamic response and early efficacy signals.