Targeting the Tumour Stroma with an Anti-FAP Antibody-Drug Conjugate
Mónica Redondo
Centro de Investigación del Cáncer (CSIC,USAL,FICUS)
Antibody–drug conjugates (ADCs) have traditionally been designed to target malignant cells directly; however, the tumour stroma represents an alternative and highly relevant therapeutic compartment. Cancer-associated fibroblasts are the most abundant cell populations within the tumour stroma and play key roles in tumour progression, extracellular matrix remodelling, drug resistance, angiogenesis, and immune suppression. These stromal fibroblasts often overexpress specific proteins, including fibroblast activation protein (FAP), whose high expression in multiple tumours makes it an attractive target for stromal-directed therapies.
OMTX105 is a novel anti-FAP ADC carrying the microtubule-disrupting payload MMAE. In a FAP-positive cellular model, OMTX105 showed selective binding and internalization, followed by intracellular payload release. This resulted in microtubule disruption, mitotic arrest, DNA damage, and apoptosis, supporting a FAP-dependent cytotoxic activity. The activity of OMTX105 was then evaluated in patient-derived cancer-associated fibroblasts from a head and neck tumour. These CAFs expressed FAP, which was efficiently recognized by OMTX105, which bound to the cell surface and was subsequently internalized. Consistent with its mechanism of action, treatment with OMTX105 induced marked cytoskeletal disorganization and phenotypic alterations in these fibroblasts. The bystander effect of OMTX105 was evaluated using a coculture model of patient-derived FAP-positive CAFs and FAP-negative tumour cells. This approach demonstrated that the binding and internalization of OMTX105 by CAFs allowed the processing and release of the payload, inducing the death of surrounding FAP-negative tumour cells.
Finally, the activity of OMTX105 was evaluated in vivo using PBMC-humanized mouse xenograft models bearing FAP-positive tumours. OMTX105 treatment induced complete tumour regression. In addition, treated mice showed increased T-cell infiltration and activation within the tumours compared with untreated controls, suggesting a possible immunomodulatory effect associated with OMTX105 treatment.
Overall, the results of this study support FAP-positive stromal targeting as a promising therapeutic strategy in solid tumours. Based on the positive results obtained, a clinical trial is to be launched in the fall of 2026.