Favorable therapeutic response after anti-Mesothelin antibody–drug conjugate treatment requires high expression of Mesothelin in tumor cells

PURPOSE: The cell surface glycoprotein Mesothelin is overexpressed in ovarian, fallopian tube, endometrial, cervical and primary peritoneal cancer and, therefore, might become a particular interesting tumor target in gynecologic oncology. However, even in malignant tumors of the same entity the level of Mesothelin expression varies between individuals, hence it can be expected that the response to Mesothelin-targeting therapies will be variable as well. In this study we explored the therapeutic potency of a novel anti-Mesothelin antibody–drug conjugate (Anetumab ravtansine) as a function of Mesothelin expression in the targeted tumor cells. METHODS: Anti-tumor activity studies were performed in human uterine xenograft tumor models that express Mesothelin at high, moderate or low levels. The antibody–drug conjugate (ADC) was applied in varying doses ranging from 2 to 15 mg/kg at variable intervals in tumor bearing SCID/beige mice and the impact on tumor growth was monitored. RESULTS: The therapeutic response to the anti-Mesothelin ADC correlated closely with the level of Mesothelin expression in tumor cells. Within the applied dose levels complete tumor regression was achieved only in tumors which expressed Mesothelin at particularly high levels (Hela cell tumors). The application of high anti-Mesothelin ADC doses less frequently was more efficious than giving lower doses at a higher frequency. CONCLUSION: The studies confirm the great therapeutic potential of Anetumab ravtansine. However, a favorable treatment outcome requires strong Mesothelin expression in tumor cells. Future clinical trials may benefit from a more rigorous selection of appropriate patients based on the level of Mesothelin expression in their tumor tissue. If, in addition, it is possible to better control side effects by introducing protective measures and by doing so to increase the maximum tolerated dose, Anetumab ravtansine has the potency to become a valuable therapeutic tool, especially in the field of gynecological oncology.