Purpose: The tumor microenvironment plays a key role in cancer development and progression and is involved in resistance to chemo- and immunotherapy. Cancer-associated fibroblast expressing fibroblast activating protein α (FAPα) is one of the predominant stroma cell types and are involved in resistance to immunotherapy.

Experimental design: We generated OMTX705, a novel antibody-drug conjugate from a humanized anti-FAP antibody linked to a new cytolysin. Here we studied its antineoplastic activity in vitro and in preclinical mouse models alone and in combination with chemotherapy as well as immunotherapy in PD1-resistant tumors.

Results: In Avatar models, OMTX705 showed a 100% tumor growth inhibition and prolonged tumor regressions as single agent and in combination with chemotherapy. Treatment re-challenge following treatment discontinuation induced additional tumor regression suggesting lack of treatment resistance. In a mouse model with a humanized immune system resistant to PD-1 inhibition, OMTX705 increased tumor infiltration by CD8⁺ T cells, induced complete regressions, and delayed tumor recurrence.

Conclusions: These data suggest that FAP-targeting with OMTX705 represents a novel and potent strategy for cancer treatment including tumors resistant to immunotherapy and support its clinical development.