Abstract B044: CBO-001, a potential first and best-in-class ADC targeting L1CAM/CD171 with potent anti-tumor efficacy in SCLC and neuroendocrine tumors

Abstract Novel targets for ADCs are clearly needed to overcome poor prognosis in patients with advanced tumors. The emerging pan-cancer target, L1 cell adhesion molecule (L1CAM/CD171) is highly expressed in various neuroendocrine and epithelial tumors with low to absent expression in normal tissues. Therefore, L1CAM/CD171 is currently clinically investigated as a target for cell therapies and as a biomarker for poor clinical prognosis. In addition, L1CAM is an excellent target for ADCs due to its high internalization rate and role in cancer cell mobility. Here we present for the first time CBO-001, a L1CAM ADC composed of a proprietary, humanized, antagonistic mAb site-specifically conjugated via a cleavable linker to an exatecan derivative. CBO-001 exhibits excellent biophysical properties: 1) low picomolar binding to a clinically validated L1CAM-epitope 2) High specificity with no observed off-target binding in >6’500 human receptors, 3) a homogenous DAR of 8.0, 4) physicochemical and plasma stability superior or comparable to trastuzumab deruxtecan and 5) silenced Fc immune function with retained FcRn receptor binding. CBO-001 further demonstrated low nM on-target cytotoxicity across various in vitro NET models, lung, ovarian, breast, gastric and colon cancer, outperforming competing L1CAM ADCs. In vitro results were validated in vivo in a small-cell lung cancer, SCLC NCI-H524 model. CBO-001 caused dose-dependent tumor regression and increased overall survival compared to standard-of-care treatment, cisplatin, by 110% and by 160% compared to the non-treated group. CBO-001-treated animals showed no target or payload-mediated hepatotoxicity, behavioral abnormalities, or adverse events at a concentration up to 10mg/kg. In conclusion, CBO-001 exhibits strong anti-tumor efficacy across L1CAM-positive indications with an excellent safety profile. Citation Format: Dominik Brücher, Christian Geraths, Michael Hackebeil, Franziska Strütt, Daniela Winkler, Christoph Schäffer, Kathrin Locher, Ruggero Della Bitta. CBO-001, a potential first and best-in-class ADC targeting L1CAM/CD171 with potent anti-tumor efficacy in SCLC and neuroendocrine tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B044.