Abstract 1882: SCR-9171, a MUC17-targeted bispecific T cell engager molecule for gastrointestinal cancer

Abstract

Abstract Background: Although advances treatments have significantly improved the survival of patients with gastrointestinal cancer in recent decades, there is still an unmet medical need for more effective treatments. A promising strategy is the use of bispecific antibodies that recruit T cells to kill cancer cells by simultaneously binding to CD3 on T cells and tumor associated antigens. CD3-based T cell engagers are highly potent therapeutic molecules with T cell cytotoxicity activities. But high CRS risk and T cell exhaustion has been observed for high affinity CD3-based T cell engagers in clinicals. Effective and safe use of these therapeutics depends on selective targeting of cancer cells and optimal CD3 affinity. MUC17, a member of the mucin family, is a transmembrane glycoprotein only expressed on the apical membrane of normal gastrointestinal mucosal epithelial cells. MUC17 is overexpressed in 23%-52% of patients with gastric cancer. Compared to the adjacent normal tissues, the expression of MUC17 protein is consistently higher in gastric cancer tissues, suggesting that MUC17 is an attractive therapeutic target for gastric cancer. Method & Results: We created MUC17/CD3 T cell engaging bispecific antibodies by starting with a nanobody humanized from camel and a low affinity CD3 antibody. Here we report the design and the promising preclinical activity of SCR-9171 molecule in vitro and in vivo. SCR-9171 induced T cell activation and had potent cytotoxicity of MUC17 positive tumor cells in vitro. However, the cytokine release was much lower than the positive control, which established with a high affinity CD3 antibody. Importantly, in mouse models with reconstituted human immune cells, SCR-9171 showed strong antitumor efficacy against MUC17-positive tumors through the activation of T cells. Tolerability and pharmacokinetics of MUC17/CD3 bispecific antibody are being assessed in cynomolgus monkey. The results demonstrated that SCR-9171 was well tolerated in a one-month repeat-dose toxicology study at 3mg/kg with no associated clinical signs or changes in body weight. Conclusion: These findings suggest that MUC17/CD3 bispecific antibody is a potential therapeutic molecule for MUC17-positive solid tumor. Citation Format: Guangcun Cheng, Yayuan Fu, Hua Zheng, ng Li, Xiaolei He, Xi Jiao, Shuhui Luan, Shuai Wang, Lei Jiang, Wenjing Li, Yun Zhang, Lei Liu, Renhong Tang. SCR-9171, a MUC17-targeted bispecific T cell engager molecule for gastrointestinal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1882.