Abstract Colorectal cancer (CRC) remains a leading cause of mortality, and patients with metastatic or chemoresistant disease still lack effective long-term treatment options. The majority of CRC tumors are microsatellite-stable (MSS), immunologically “cold” and respond poorly to immune checkpoint inhibitors (ICIs), underscoring the need for novel targeted and combination strategies to improve outcomes in these high-risk patient populations. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is an attractive target as it is frequently overexpressed in colorectal, gastric, esophageal and other cancers and shows restricted expression in healthy tissues. In CRC, LGR5 prevalence is high and expression is associated with advanced disease and poor prognosis. LGR5-positive CRC cells display enhanced stemness, including increased tumorigenicity and therapy resistance. CDR609 is a first-in-class T cell engager for the treatment of LGR5-expressing solid tumors, based on the same M-gager® format as CDR404 currently in Phase I (NCT06402201). Our study provides preclinical pharmacology data, including potency, selectivity and novel mechanistic insights. Given cetuximab’s established benefit in RAS wild-type metastatic CRC, we additionally investigate the in vitro activity of CDR609 in combination with cetuximab compared to CDR609 alone. CDR609 demonstrates potency in co-cultures of LGR5+ cancer cell lines with human PBMCs, correlating well with target expression levels. It shows robust activity across multiple CRC subtypes, including microsatellite instability-high (MSI-H), as well as MSS and KRAS mutant models, often resistant to ICIs and/or EGFR inhibitors. CDR609 efficiently triggers granzyme B release even at low E: T ratios (down to 1: 1), indicating that it has the potential to achieve efficacy in tumors with low T cell infiltration (“cold tumors”). In addition to 2D cultures, CDR609 also shows activity on 3D spheroids of LGR5+ cancer cell lines. Since treatment with EGFR inhibitors is accompanied by upregulation of LGR5, we evaluated CDR609 in combination with cetuximab. Combination treatment enhances the activity of the M-gager® compared to M-gager® alone due to increased target expression. Mechanistically, CDR609 does not compete with R-spondins for binding to LGR5, minimizing potential interference with Wnt signaling, and does not trigger proliferation of LGR5+ cells, aspects which are crucial for safety. In conclusion, CDR609 potently targets LGR5+ cancer cells across varying target levels and hard-to-treat subtypes such as MSS and KRAS mutant CRC. Its activity at low E: T ratios supports efficacy in immunologically “cold” tumors, while cetuximab combination enhances potency via LGR5 upregulation. These data support the high potential of CDR609 in hard-to-treat cancers like CRC and studies are ongoing to enable initiation of a first-in-human clinical trial. Citation Format: Athanasia Dasargyri, Alessio Vantellini, André Fonseca, Anna Howald, Blaz Pavlovic, Alice Langer, Martina Priola, Nora Wettstein, Zoi Barou, Cedric Kiss, Hannes Merten, Sophie Barsin, Stephanie Jungmichel, Leonardo Borras. Mechanistic insights into the pharmacology of CDR609 support high potential as a targeted immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB269.
Dasargyri et al. (Fri,) studied this question.