Abstract 6062: A novel bi-specific antibody targeting CD39 and PD-L1 for enhanced cancer immunotherapy

Abstract While immune checkpoint inhibitors have revolutionized cancer treatment, there remains a significant unmet need for more potent strategies to bolster anti-tumor immunity. This study introduces OriA631-B, a pioneering bi-specific antibody designed to simultaneously engage CD39 and PD-L1. By disrupting both the metabolic checkpoint CD39 and the immune checkpoint PD-L1, OriA631-B aims to amplify therapeutic efficacy.Leveraging advanced antibody engineering, OriA631-B was meticulously crafted to exhibit optimal binding affinity and specificity for its intended targets. In vitro studies revealed that OriA631-B, rooted in a clinically validated PD-L1 antibody, effectively suppressed CD39-mediated adenosine generation, thereby invigorating effector T cell function and proliferation. In vivo investigations utilizing syngeneic tumor models demonstrated that OriA631-B treatment significantly curtailed tumor growth compared to monotherapy or combination therapies. Safety assessments indicated a favorable toxicity profile, with no substantial adverse events observed.Collectively, these findings highlight the promising potential of OriA631-B as a novel immunotherapeutic agent in cancer treatment. By concurrently targeting CD39-mediated immune suppression and PD-L1-mediated T cell exhaustion, this bi-specific antibody may circumvent resistance mechanisms and enhance T cell engagement with tumor cells, ultimately improving patient outcomes. Further clinical evaluation is warranted to fully assess the therapeutic potential of this innovative bi-specific antibody in cancer immunotherapy. Citation Format: Ze Yang, Xiaopei Li, Zhongliang Li, Yongfa Chen, Huajing Wang, Xu He, Hongwei Sun, Xiaowen Lin, Ligong Lu, Xiaowen He, Meixiao Zhan, Ke He, Wei Zhao. A novel bi-specific antibody targeting CD39 and PD-L1 for enhanced cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6062.