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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 is 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 PD-1–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 rechallenge 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.

Additional Materials and Methods information not included in the article text, and detailed description of the patient tumors from which xenograft models have been derived from

S1-S7 all supplementary figures with their legends: S1:Figure S1. OMTX705 binding and internalization in HT1080-WT, -FAP and CAFs S2:Weight change of mice bearing Panc 007, Lung 024 and Breast 014 tumors. S3: OMTX705 Activity in the Immunodeficient Patient Derived Xenografts (PDX) Models of Ovarian Cancer. S4: FAP immunostaining in frozen tumor samples from humanized mice bearing CTG-0860 NSCLC PDX tumor. S5: Separate fluorescent staining of human IgG, Rab7 and nuclei in OMTX705 and OMTX005 treated HT1080-FAP cells (complements the merged image of figure 4C) S6: Immunohistochemical analysis of payload, OMTX005 and OMTX705 distribution in tumors from Panc 007 model. S7: Schematic summary of findings and proposed mechanism of action of OMTX705.

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 is 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 PD-1–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 rechallenge 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.