Abstract A126: CDR609: A First-in-Class LGR5-targeted T Cell Engager for treatment of Colorectal Cancer and other solid tumors

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Despite progress in screening and therapeutic strategies, a substantial proportion of patients are diagnosed at advanced stages or experience disease recurrence, both of which are associated with poor prognosis. Current standard-of-care treatments, including chemotherapy, targeted agents and immunotherapy, are often limited by the emergence of drug resistance or the immunologically ¨cold¨ nature of CRC. Immunotherapies failed to benefit the vast majority of CRC patients beyond the mismatch repair deficient (dMMR) subtype. These challenges highlight the need for more effective targeted immunotherapies capable of deep and durable responses. LGR5 (Leucine-rich repeat-containing G protein-coupled receptor 5) has high expression levels in CRC and other solid tumors, including gastric, pancreatic, and ovarian cancer. In CRC, LGR5 prevalence is high, and expression correlates with poor clinical outcomes. Physiologically, LGR5 expression is limited to adult stem cells, such as in intestinal crypts and hair follicles. In contrast, LGR5 is frequently overexpressed and broadly distributed in malignant tissues, making it a suitable candidate for therapeutic targeting. CDR609 is a first-in-class T cell engager (TCE) for the treatment of LGR5-expressing solid tumors, based on the same M-gager® format as CDR404 (Phase I, NCT06402201). It binds a specific epitope on LGR5 critical for facilitating immunological synapse formation and subsequent T cell activation. With an LGR5 monovalent affinity in the pM range, CDR609 shows very efficient cancer cell killing of LGR5+ cancer cell lines in co-cultures with human PBMCs. This is accompanied by upregulated expression of activation (CD69, CD25) and proliferation (Ki67) markers on CD8+ T cells. T cell activation was further confirmed by the presence of cytokines and cytolytic molecules detected in culture supernatants, including IFNγ and granzyme B. The excellent specificity profile was demonstrated by the lack of relevant T cell reactivity against various LGR5-negative cell lines, as well as normal human cells from different tissues. The biophysical properties of the molecule were optimized for an ideal developability profile. Stability and solubility measurements predict good shelf life and in vivo stability. In conclusion, CDR609 efficiently activates T cells and kills LGR5-positive cancer cells. It has the potential to generate robust immunological activity in patients with CRC and other cold tumors, as demonstrated in Phase I with the CDR404 M-gager® in patients with a variety of cold tumors. CDR609 also shows high specificity for LGR5, and an overall safe profile in the presence of normal human cells. Future studies will include in vivo efficacy testing and a broader range of cellular assays using ex vivo patient-derived tissues and cultured cells as part of the preclinical studies that will be included in the IND application. Citation Format: Athanasia Dasargyri, Sophie Barsin, Fabian Scheifele, Philipp Richle, Nagjie Alijaj, Anna Sobieraj, Romina Doerig, Hannes Merten, Martina Priola, Blaz Pavlovic, Marko Keric, David Schurter, Cedric Kiss, Ariadna Vilarrasa, Stephanie Jungmichel, Matteo Morotti, Swethajit Biswas, Christian Leisner, Leonardo Borras. CDR609: A First-in-Class LGR5-targeted T Cell Engager for treatment of Colorectal Cancer and other solid 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 A126.