A NOVEL IMMUNOSTIMULATORY PD-L1/OX40 TETRAVALENT BISPECIFIC ANTIBODY FOR CANCER IMMUNOTHERAPY

Abstract Single agent immune checkpoint therapy has shown substantial and durable clinical activity in many tumor types; however, only a fraction of the patients could benefit from this approach. To improve beyond the anti-PD-1/PD-L1 treatment options, bispecific antibodies (BsAb) that combines PD-L1 blockade and conditional co-stimulatory receptor activation simultaneously in one molecule have been developed and demonstrated superior anti-tumor activity in pre-clinical models. However, many of these PD-L1 based BsAb faced challenge in clinical development due to insufficient activity or unexpected toxicity. Here, we demonstrated that OX40 might be a more suitable partner for PD-L1 based BsAb design than other agonistic targets (CD27 and 4-1BB, etc.) currently in clinical studies. A novel Fc silenced tetravalent PD-L1/OX40 (EMB-09) BsAb targeting optimal OX40 binding epitope has been developed based on EpimAb’s proprietary FIT-Ig® technology. Results showed that EMB-09 maintained the parental mAb binding characteristic and retained the functional properties of each parental mAb including OX40 agonistic as well as PD-L1/PD1 inhibitory pathways. In addition, EMB-09 induced OX40 activation only in the context of PD-L1 engagement. Concurrent PD-L1/PD-1 blockade and OX40 co-stimulation by EMB-09 led to synergistic activation of T cell in vitro and exerted superior anti-tumor activity in mouse tumor models compared to anti-PD-L1 mAb. The underlining mechanism was extensively analyzed, which indicated an increased CD8+ tumor-infiltrating T-cells (TIL) as well as enhanced CD8 TIL activation status upon EMB-09 treatment. Additionally, EMB-09 was well tolerated in cynomolgus monkeys at high dose levels with a favorable safety and PK profile in a GLP-TOX study. In conclusion, as a PD-L1/OX40 BsAb with a novel biology mechanism, EMB-09 demonstrated a markedly improved anti-tumor activity compared to anti-PD-L1 mAb. The first-in-human clinal study of EMB-09 has been initiated (NCT05263180).