Abstract 2735: High affinity and potent anti-tumor efficacy of Nivo813, an anti-PD-1/ALK-1 bispecific antibody, in pre-clinical studies for solid tumors

Abstract

Abstract Background: The activin-like kinase receptor 1 (ALK-1, encoded by ACVRL1) is a member of the transforming growth factor β (TGF-β) superfamily. Combination treatment using anti-PD-1/PD-L1 agents with anti-angiogenetic reagents might bring additional benefits, such as establishing a favorable TME leading to better responses towards immunotherapy. In the phase II clinical trial (NCT03893695) of combination therapy of ALK-1 (GT90001) and Nivolumab for the second line therapy in patients with metastatic hepatocellular carcinoma (“HCC”) in Taiwan, among the 20 evaluable patients, the overall response rate is 40%, and the side effects were well tolerated and manageable. Nowadays, the combination of GT90001 and nivolumab shows a remarkable long-tail effect, since 7 patients are still alive as of March 30, 2023, 6 of them had received no further systematic anti-tumor therapy after trial completion. Among them, 4 patients are still on progression free status. Our pre-clinical data demonstrated that Nivo813 has improved cell-binding potency and potent anti-tumor effects, lighting up its potential capacity as a therapeutic drug in the treatment of human cancers. Methods: The antigen binding activity of Nivo813 with PD-1 and ALK-1 were assessed by ELISA, Fortebio and flow cytometry. Endothelial cell tube formation assay was performed to identify the anti-angiogenesis function of Nivo813. The anti-tumor activity of Nivo813 was investigated in PBMC implanted with MDA-MB-231 breast cancer cells. Results:Nivo813 could specifically bind to human PD-1 and ALK-1 with high affinity. Intriguingly, Nivo813 was found to have much higher affinity (40-fold, nM) to cell surface PD-1 than that of nivolumab. Meanwhile, Nivo813 exhibited dose-dependent anti-angiogenesis activity in vitro. Nivo813 demonstrated greater anti-tumor efficacy compared to nivolumab in mice model. Conclusions: Nivo813, a dual-blocking anti-PD-1/ALK-1 bispecific antibody, shows improved binding potency to cell surface PD-1 and ALK-1 simultaneously, and displays dose-dependent anti-angiogenesis in vitro and great anti-tumor efficacy in vivo, supporting its clinical potentials for the treatment of human cancers. Citation Format: Qingqing Zhou, Rong Tang, Lanfang Zhuang, Jianyu Huang, Jiang Qian, Zhihua Ren, Youzhi Tong. High affinity and potent anti-tumor efficacy of Nivo813, an anti-PD-1/ALK-1 bispecific antibody, in pre-clinical studies for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2735.