OMTX705, a Novel FAP-Targeting ADC Demonstrates Activity in Chemotherapy and Pembrolizumab-Resistant Solid Tumor...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• The tumor microenvironment significantly influences cancer progression and treatment resistance.
• Cancer-associated fibroblasts expressing fibroblast-activating protein alpha (FAPα) are key components of the tumor microenvironment and contribute to immunotherapy resistance.

Purpose of the Study:

• To evaluate the antineoplastic activity of OMTX705, a novel antibody-drug conjugate targeting FAPα.
• To assess OMTX705 efficacy alone and in combination with chemotherapy and immunotherapy in preclinical models, including PD-1-resistant tumors.

Main Methods:

• Generation of OMTX705, an antibody-drug conjugate comprising a humanized anti-FAP antibody and a novel cytolysin.
• In vitro and in vivo studies using preclinical mouse models, including Avatar models and a humanized immune system model resistant to PD-1 inhibition.

Main Results:

• OMTX705 demonstrated 100% tumor growth inhibition and induced prolonged regressions as a single agent and in combination with chemotherapy in Avatar models.
• In a PD-1-resistant model, OMTX705 increased CD8+ T cell infiltration, achieved complete tumor regressions, and delayed recurrence.
• Rechallenge studies suggested a lack of treatment resistance.

Conclusions:

• Targeting FAPα with OMTX705 presents a novel and potent strategy for cancer treatment.
• OMTX705 shows promise for treating tumors resistant to immunotherapy, supporting its clinical development.