Oncogene. 2026 Jul 07.
Mark Primeaux,
Zeina Nehme,
Iram Fatima,
Frank Jühling,
Emilie Crouchet,
Jade Brochon,
Alberto Toso,
Catherine Schuster,
Amar B Singh,
Thomas F Baumert,
Punita Dhawan.
Claudin-1 (CLDN1), a tight junction protein overexpressed and mis-localized in colorectal cancer (CRC), plays a critical role in tumor progression, stemness, and therapy resistance. Integrative analyses of bulk and single-cell transcriptomic datasets revealed that CLDN1 is enriched in stem-like CRC cells, increases during metastatic progression, and is associated with microsatellite stable disease. High CLDN1 expression correlates with epithelial-to-mesenchymal transition and activation of oncogenic pathways including AKT/mTOR, Myc, and NF-κB. Here, we evaluate the therapeutic efficacy of an investigational humanized monoclonal antibody (H3L3) directed against overexpressed non-junctional CLDN1 in preclinical models of CRC. In xenograft mouse models and patient-derived organoids (PDOs), CLDN1 mAb significantly reduced tumor growth in CLDN1-expressing tumors. Mechanistically, CLDN1 mAb disrupted CLDN1-mediated signaling, notably inhibiting the AKT/mTOR pathway. CRISPR-mediated CLDN1 knockout abolished H3L3 efficacy, confirming target specificity. Transcriptomic analysis of PDOs treated with H3L3 revealed broad suppression of stemness, oncogenic signaling, and hallmark cancer pathways. Single-cell analysis further demonstrated that targeting CLDN1 modulates cellular plasticity, driving stem-like tumor cells toward a more differentiated epithelial phenotype. Together, these findings establish anti-CLDN1 monoclonal antibodies as a promising therapeutic approach for CRC. The selective binding of CLDN1 mAb to tumor-associated exposed and overexpressed CLDN1, along with its capacity to inhibit key oncogenic pathways and reprogram cancer cell states including tumors with different mutations conferring resistance to standard of care, underscores its potential to improve treatment outcomes in patients with CLDN1-expressing CRC.