Abstract 2131: Glycosylated protein targets open access to multiple tumor indications for different therapeutic modalities

Abstract Using advanced O-glycoproteomics we pinpointed relevant glycopeptide epitopes and developed a highly cancer-specific, humanized monoclonal antibody (R800). This antibody binds to truncated O-glycans in the context of a peptide backbone with low nanomolar affinity. The crystal structure of R800 provides insights into its binding specificity showing direct interaction with both peptide and the truncated glycan. Development of a companion diagnostic assay based on immunohistochemistry with the humanized therapeutic antibody confirmed the specificity of R800 across multiple epithelial cancers. This included selective binding to 20-30% of both primary and metastatic triple negative breast, lung, pancreatic, colorectal, and ovarian cancers. There was no binding to healthy tissues. The versatility of R800 allows the application of the mAb in multiple therapeutic modalities, including chimeric antigen receptor T-cell therapies (CAR-T cells) and antibody-drug conjugates (ADCs). In CAR-T cell applications using R800's antigen-binding domain demonstrated potent, selective cytotoxicity against R800-target expressing cancer cells in vitro in vivo in CDX models. In ADC applications, R800 formulated with either the anti-mitotic agent, monomethyl auristatin E payload (R800-MMAE) or with the topoisomerase 1 inhibitor payload, exatecan (R800- exatecan) show potent activity in vitro (EC50 ∼1nM) across multiple cell lines. Both R800 ADCs effectively eliminated tumors in preclinical PDX models, including lung, ovarian, and TN breast PDx models with a MED of 2mg/kg. By targeting the cancer-specific truncated O-glycans recognised by R800, we exploit a novel target space offering unparalleled cancer selectivity. This strategy holds significant potential for enhancing the efficacy and safety of treatments for solid tumors. Citation Format: Aaron C. Groen, Nisha Shrestha, Boris Klebanov, Constantine Theodoropulos Constantine Theodoropulos, Hans H. Wandall. Glycosylated protein targets open access to multiple tumor indications for different therapeutic modalities [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 2131.