Abstract 3270: Dual blockade of PD-L1 and LAG-3 using a bispecific antibody improves anti-tumor immunity

Abstract

Abstract Background: Anti-PD-1/PD-L1 treatments are effective in a fraction of patients with advanced malignancies. However, the majority of patients still do not respond. Resistance to cancer immunotherapy can be mediated by additional immune checkpoints. Lymphocyte-activation gene 3 (LAG-3) is a member of the Ig superfamily and participates in immune suppression. Combination of anti-PD-1 and anti-LAG-3 showed synergistic anti-tumor effect in preclinical mouse models and early clinical trials. Here, we develop IBI323, an anti-PD-L1/LAG-3 bispecific antibody, which preserves the dual pathway blockade function while processes new biological functions. Material & Methods: The binding affinity of IBI323 to antigens were measured by Fortebio and confirmed at cellular level using PD-L1 overexpressing cells and primary T cell. IBI323 was also assessed by ELISA for PD-1 and LAG-3 pathway blocking function. IBI323 mediated PD-L1+ and LAG-3+ cells bridging was evaluated by flow cytometry. Anti-tumor activity of IBI323 was evaluated in human PD-L1 knock-in mice bearing PD-L1 overexpressing MC38 tumors. Besides tumor growth, the frequencies and quality of the tumor-specific T cells were assessed by flow cytometry. In addition, florescence labeled antibodies was used for detecting the biodistribution of IBI323 in vivo. Results: IBI323 bound to PD-L1 and LAG-3 with high affinity (KD <1 nm). At cellular level, IBI323 bound to PD-L1 overexpressing cells and LAG-3+ T cells in a similar manner to parental antibodies. IBI323 was able to block PD-1/PD-L1 and LAG3/MHCII interactions simultaneously. Moreover, bridging between PD-L1+ cells and LAG-3+ cells was observed in the presence of IBI323 in vitro. Correspondingly, IBI323 was mainly distributed at the location of PD-L1+ tumor in vivo. In mice harboring established PD-L1+ MC38 tumor, IBI323 treatment was superior to combination of individual anti-PD-L1 and LAG-3 antibodies. The better activity of IBI323 treatment was reflected by an enhanced number of tumor-specific CD8+ cytotoxic T cells. Conclusions: We developed a novel bispecific antibody against PD-L1 and LAG-3, which resulted in dramatic tumor growth inhibition. The anti-tumor efficacy of IBI323 was better than either monotherapy or anti-PD-L1 and LAG-3 combination treatment. Based on the encouraging preclinical results, IBI323 could soon be evaluated in clinical trials. Citation Format: Haiqing Ni, Yajing Qiu, Hua Jing, Pan Zhang, Bingliang Chen, Zhihai Wu, Shuaixiang Zhou, Michael Yu, Junjian Liu. Dual blockade of PD-L1 and LAG-3 using a bispecific antibody improves anti-tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3270.