Abstract 4430: Sacituzumab-Interferon beta mutein fusion protein, ABN202 (anti Trop2-interferon beta mutein), is a potent therapeutics for Trop-2-positive urothelial cancer

Abstract

Abstract Background: Trop2, trophoblast cell-surface antigen 2, is a type 1 transmembrane glycoprotein overexpressed in many solid tumors such as breast, lung, pancreatic, gastric, colon, urothelial cancer. Overexpression of Trop2 is associated with aggressive disease progression and poor prognosis. Recently, Trop2 targeting antibody-drug conjugate such as sacituzumab-govitecan (Trodelvy®) was approved for the treatment of triple-negative breast cancer and urothelial cancer (UC) patients. Interferon-beta (IFN-beta), a pleiotropic cytokine, can induce direct/in-direct tumor killing and activate anti-tumor immune response in tumor microenvironments. However, it is challenging to develop IFN-beta as an anti-cancer agent due to its low biophysical properties, short half-life, and the systemic toxicity. Previously, we developed IFN-beta mutein (ABN102), which showed improved stability and biophysical properties compared to wild-type IFN-beta. We hypothesis to reduce any toxicity of ABN102 by fusing with tumor targeting antibody. In this study, we generated antibody cytokine fusion protein (ABN202), anti Trop2-interferon-beta mutein, and evaluated the efficacy of ABN202 against Trop2-positive UC cell line models. Method & Result: We aimed to determine the direct anti-cancer efficacy of ABN202 using Trop2-positive UC cell lines and the indirect immune cell mediated effect of ABN202 using Trop2-positive UC cell lines co-cultured with human peripheral blood mononuclear cell (PBMC). The in vivo efficacy of ABN202 was further confirmed in Trop2 positive tumor mouse model. Our results revealed that ABN202 directly inhibited proliferation and activates the apoptosis-related signaling mechanisms via Type 1 IFN signaling, showing better efficacy than either anti Trop2 antibody (sacituzumab) or ABN102 alone. ABN202 induces the activation of PBMC subsets and enhanced immune cell-mediated cancer cell killing when UC cell lines were co-cultured with PBMC. The anti-cancer efficacy of ABN202 were confirmed in Trop2-positive tumor mouse model. Conclusion: We evaluated the direct and indirect anti-cancer efficacy of ABN202 (anti Trop2-interferon-beta mutein) in Trop2-positive urothelial cancer. Our results support that ABN202 is a potent drug candidate in Trop2-positive urothelial cancer by directly inhibiting tumor growth and activating anti-cancer immune responses through type 1 IFN signaling. Citation Format: Jiyang Lee, Myeung-Ryun Seo, Heegeon Park, YeongMun Kim, Saehyung Lee, Na Young Kim, Chan Gyu Lee, Hae Min Jeong, Jun Young Choi, Young kee Shin. Sacituzumab-Interferon beta mutein fusion protein, ABN202 (anti Trop2-interferon beta mutein), is a potent therapeutics for Trop-2-positive urothelial 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 4430.