Abstract 7209: Status-agnostic therapy of breast cancer using antibodies targeting O-glycosylated proteins

Abstract We have developed a novel antibody-drug conjugate (ADC), based on the mAb L100, that selectively targets a O-GalNAc-glycoprotein expressed in approximately 20% of all breast cancer. Unlike many ADC programs targeting Breast Cancer, L100 recognizes cancer-specific O-glycosylated versions of proteins do not present on normal tissues circumventing adverse events from on target off tumor binding to healthy tissues. The crystal structure of L100 provides insights into its binding specificity and affinity. L100 exhibits low nanomolar affinity (0.83nM) to the glycoprotein target and has also been developed as a companion diagnostic assay, further validating its potential as a therapeutic target. L100 is conjugated to the microtubule-disrupting agent MMAE and the topoisomerase inhibitor exatecan via a site-specific β-glucuronidase-cleavable linker. This linker is stable in plasma, but selectively releases the payload in tumor tissues, which exhibits a high expression pattern of beta-glucuronidase. In preclinical studies, the L100 ADC (LCB22A) demonstrated potent and selective cytotoxicity against various cancer cell lines (EC50=∼4.4 nM) and effectively eliminated tumors in breast cell-derived xenograft (CDX) and patient-derived xenografts (PDX) with MED = ∼2mpk. Importantly, L100-MMAE (LCB22A-MMAE) and L100-exatecan (LCB22A-exatecan) were well-tolerated in cynomolgus monkey toxicity studies, with no significant adverse events observed. Additionally, the ADC selectively killed target cells in a human mixed organotypic cancer model without affecting healthy cells, indicating excellent tolerability and safety. By specifically targeting cancer-specific O-glycans expressed only in cancer tissues and employing a tumor-selective payload release mechanism, L100 ADC (LCB22A) offers a promising and safe therapeutic option for treating breast cancer while avoiding the on-target off-tumor toxicity that plague other ADC therapies. Citation Format: Aaron C. Groen, Nisha Shrestha, Boris Klebanov, Byeongjun Yu, Beom Yong Lee, Yun-Hee Park, Chul-Woong Chung, Constantine Theodoropulos, Hans H. Wandall. Status-agnostic therapy of breast cancer using antibodies targeting O-glycosylated proteins [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 7209.