Abstract LB269: Mechanistic insights into the pharmacology of CDR609 support high potential as a targeted immunotherapy

作者：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 · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-lb269 · 研究领域：Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research、Monoclonal and Polyclonal Antibodies Research

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...