Abstract 2943: SWY2321, a novel topoisomerase I inhibitor linked bispecific ADC targeting EGFR/cMet, exhibits potent anti-tumor efficacy

Abstract EGFR and cMet are two important clinically validated targets in cancer therapy. They exhibit overexpression across various cancer types with a poor prognosis. The signaling pathways of EGFR and cMet demonstrate intricate interconnections, with evidence suggesting that activation of one pathway can trigger the other. These interactions contribute to augmented cell proliferation, survival, invasion, ultimately tumor growth as well as therapeutic resistance. Consequently, targeting both EGFR and cMet has the potential to improve treatment in patients with solid tumors characterized by EGFR and/or cMet dysregulated pathways. SWY2321 is comprised of a bispecific antibody against EGFR/cMet, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent. The ADC was constructed on the backbone of the clinically validated monovalent bispecific IgG platform and was engineered with fine-tuned affinity on EGFR and cMet, with the aim of enhancing tumor inhibition capacity while reducing EGFR and/or cMet-driven toxicity in normal tissues. SWY2321 demonstrated in vitro binding to all the tested cancer cell lines with various expression of EGFR and cMet, and showed higher internalization and cytotoxicity on the tumor cells co-expressing EGFR and cMet than single targeted ADC or first in class ADC. Furthermore, SWY2321 had potent efficacies on the tumor xenograft models of different malignant types including non-small cell lung cancer (NSCLC), gastric cancer (GC), cutaneous squamous cell cancer (CSCC), and with various expression levels of these two targets, including EGFRHighcMetLow, EGFRLowcMetHigh, EGFRmoderatecMetmoderate and EGFRLowcMetLow. The tumor inhibition efficacies of SWY2321 on these models were superior to first in class ADC, and superior to or equivalent to single-targeted ADCs given at the same dose with SWY2321. Especially in EGFR/cMet co-expressed NSCLC NCI-H1975 tumor model, SWY2321 showed excellent efficacy at 1.5 mg/kg single administration. In summary, the promising efficacy of SWY2321 supports that SWY2321 can be an effective treatment targeting multiple EGFR- or cMet- expressing solid tumors. Citation Format: Jinyu Yang, Jing Qiao, Mo Dan, Xiwu Hui, Bing Yao, Can Yuan, Miaomiao Wei, Xiao Li, Xuening Lv. SWY2321, a novel topoisomerase I inhibitor linked bispecific ADC targeting EGFR/cMet, exhibits potent anti-tumor efficacy [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 2943.