Abstract 5831: ABN202 (αTROP2), a sacituzumab-interferon-beta mutein fusion protein: a novel approach beyond antibody-drug conjugate therapeutics in ADC-naïve and ADC-refractory cancers

Abstract Trophoblast cell surface antigen 2 (TROP2) is a cell-surface glycoprotein overexpressed in various solid tumors, including triple-negative breast cancer (TNBC), hormone receptor-positive breast cancer (HR+ BC), and non-small cell lung cancer (NSCLC). TROP2-targeting antibody-drug conjugates (ADCs) such as Sacituzumab-govitecan (SG) and Datopotamab deruxtecan (Dato-DXd) demonstrated promising clinical efficacy in patients with TROP2-positive cancers. However, TROP2-targeting ADCs exhibit a high incidence of adverse events, a short duration of response, and frequent recurrence. Therefore, there is an unmet medical need for treatments beyond ADC therapeutics, particularly for ADC-naïve and ADC-refractory patients. ABN202 is an antibody-cytokine fusion protein platform that fuses a potent cytotoxic and immune-modulating cytokine, interferon-beta mutein (IFN-β mutein), with an antibody via flexible protein linker. In previous studies, ABN202 utilizing the TROP2-targeting antibody, Sacituzumab (ABN202, αTROP2), demonstrated potent anti-tumor efficacy by inhibiting cancer cell growth and activating anti-tumor immunity within the tumor microenvironment. In this study, we compared the in vitro and in vivo anti-cancer efficacy of ABN202 (αTROP2) with those of SG and Dato-DXd in ADC-resistant preclinical models, as well as in xenograft and human IFNAR knock-in (hIFNAR KI) mouse models. The preclinical toxicity profiles of SG, Dato-DXd, and ABN202 (αTROP2) were evaluated using human immune cells and hIFNAR KI mouse models. In conclusion, ABN202 (αTROP2) demonstrated potent anti-cancer efficacy and a tolerable safety profile compared to SG and Dato-DXd. Our findings suggest that ABN202 (αTROP2) represents a novel therapeutic approach beyond ADCs for both ADC-naïve and ADC-refractory cancers. Citation Format: Hee Geon Park, Hyun Kyung Lee, Myeung Ryun Seo, Soo Jin Ryu, Sungyoul Hong, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Young Kee Shin, Jun Young Choi. ABN202 (αTROP2), a sacituzumab-interferon-beta mutein fusion protein: a novel approach beyond antibody-drug conjugate therapeutics in ADC-naïve and ADC-refractory cancers [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 5831.