Abstract 1581: Two novel antibodies targeting different tumor-associated carbohydrate (TACA) antigens for the treatment of solid tumors show promising preclinical activity using different modes of action

Abstract Tumor-associated carbohydrate antigens (TACAs) are short oligosaccharides that are often overexpressed on the surface of cancer cells. They are derived from changes in glycosylation pathways associated with malignancy, which lead to overproduced or aberrant structures, and represent a still unexplored target class for cancer therapy. We focus on the generation of antibodies against these specific and difficult antigens and were able to obtain two high-affinity monoclonal antibodies (mAbs), TCX-101 and TCX-201, against two distinct TACA structures that are highly expressed across a broad range of cancer indications. Both mAbs show superior affinity and specificity to their target compared to previously generated ones, as assessed by glycan array, flow cytometry, and immunohistochemistry or immunofluorescence. By investigating the characteristics of our glycan targets, we explored different modes of action to tailor the most effective treatment. Previously, our team has shown that TCX-101 can be effectively used as an antibody-drug conjugate (ADC), which showed encouraging results in vivo against breast and small cell lung cancer (SCLC). In addition, we here present TCX-101 in a bispecific T-cell engager (TcE) format, showing efficient in vitro T-cell activation and killing of cancer cells from different indications endogenously expressing low (SW837), medium (LoVo) to high levels (MCF7) of our TACA target already at an effector:target ratio of 4:1 with antibody concentrations in the pico- to low nanomolar concentration range, i.e. IC50 of 9 nM (SW837), 0.13 nM (LoVo) and 0.0078 nM (MCF7), respectively. In vivo evaluation of this TcE is currently investigated using cell-line derived xenograft models in humanized mice. TCX-201, targeting a different TACA, is currently being evaluated as an ADC with two different payloads, monomethyl Auristatin E (MMAE) and Exatecan (XTC). In vitro studies show effective killing of various pancreatic (e.g. high expressing HuP-T4 cells with an IC50 for MMAE payload of 0.3 nM) and colon cancer cell lines expressing different levels of the target (e.g. Colo-205 (high expressing) with an IC50 of 0.013 nM or LS180 (medium expressing) with an IC50 of 4.7 nM), and high efficacy for both payloads in a xenograft mouse model using HuP-T4 pancreatic cancer cells. In conclusion, our antibodies against TACAs represent new promising treatment options for different cancer indications and can be effectively employed with different modes of action, depending on the target characteristics. Citation Format: Francesco Muraca, Wiebke Winkler, Gustavo M.S.G. Moreira, Fausto G. Gomes, Karla E. G. Soto, Samina Naz, Peter Sondermann, Matthias Ocker. Two novel antibodies targeting different tumor-associated carbohydrate (TACA) antigens for the treatment of solid tumors show promising preclinical activity using different modes of action [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 1581.