Abstract 6084: YH32364 (ABL104), a bispecific antibody against EGFR and 4-1BB, demonstrates potent anti-tumor efficacy through tumor-directed 4-1BB agonism

Abstract The epidermal growth factor receptor (EGFR) regulates cellular proliferation, differentiation, and survival, making it a critical target in cancer therapy. While EGFR-targeted therapies show efficacy in EGFR-overexpressing cancers, their use is limited by the frequent onset of drug resistance, necessitating novel approaches. Combining EGFR inhibitors with immunotherapy, such as targeting the costimulatory receptor 4-1BB (CD137) on activated T and NK cells, holds potential to improve anti-tumor responses. Recent advances in bispecific antibodies (bsAbs) allow for dual targeting strategies. Specifically, bsAbs containing T cell engagers improve immune responses by guiding T cells directly to tumor cells, thus enhancing immune targeting. Additionally, bsAbs that engage both 4-1BB and tumor-associated antigens (TAAs) amplify T cell activation within the tumor microenvironment, increasing the precision and efficacy of immune responses.A novel therapeutic agent, YH32364, was designed to address EGFR-related drug resistance through a dual mechanism: tumor-directed 4-1BB agonism combined with EGFR signal blockade. This approach aims to enhance tumor-localized 4-1BB activation while reducing the risk of excessive 4-1BB stimulation. Its binding affinity and activity were determined using surface plasmon resonance (SPR), a cell-based 4-1BB bioassay and immune mediated tumor killing assays using human peripheral blood mononuclear cells (hPBMCs). In vivo anti-tumor efficacy and antitumor immune response of YH32364 were assessed in mice models. 4-Week repeated dose monkey GLP toxicity study was also conducted. SPR analysis revealed high-affinity binding of YH32364 to both human EGFR and 4-1BB. YH32364 demonstrated strong 4-1BB activation and anti-tumor effects in EGFR-expressing cancer cell lines, as shown by IFN-γ secretion and subsequent tumor cell lysis. In vivo studies confirmed dose-dependent tumor regression by YH32364 and the induction of adaptive immunity in h4-1BB KI mouse models. Additionally, YH32364 recruited immune cells into EGFR-positive tumors, leading to modulation of the tumor microenvironment. As anticipated, no signs of hepatotoxicity were observed in a 4-week toxicity study in monkeys with no severe adverse findings on mortality, body weight, hematology, clinical chemistry, and other parameters. etc.Collectively, non-clinical studies demonstrate that YH32364 exhibits EGFR-dependent antitumor activity and induces long-term immunologic memory without hepatotoxicity. These findings suggest that YH32364 offers distinct advantages over conventional EGFR-targeted therapies by leveraging 4-1BB-mediated immunotherapy. Citation Format: Jae-Won Lee, Yangsoon Lee, Eunjung Lee, Hanna Hong, Byeong-Yun Ahn, Jangbeen Kyung, Young Bong Park, Junhwan Kim, Kyeongsu Park, Wonjun Son, Jaehyun Eom, Hanbyul Lee, Kyeongnang Moon, Yelim Park, Jonghwa Won, Se-Woong Oh, Yeul Hong Kim. YH32364 (ABL104), a bispecific antibody against EGFR and 4-1BB, demonstrates potent anti-tumor efficacy through tumor-directed 4-1BB agonism [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 6084.