Preclinical evaluation of a novel MET antibody-drug conjugate in uveal melanoma models

Uveal melanoma is the most common primary intraocular malignant tumor in adults. These tumors are characterized by mutations in G-proteins (GNAQ and GNA11) and high expression of MET, a receptor tyrosine kinase. While inhibition of MET signaling delays the development of uveal melanoma metastases in preclinical models (possibly by inhibiting cell migration), primary tumor growth is not inhibited, indicating a lack of dependence on the MET pathway. Thus, treatment of established metastatic uveal melanoma with MET signal blockers is unlikely to be effective. However, the high expression of MET protein in metastatic uveal melanoma presents an opportunity to directly kill tumor cells with a MET-targeted antibody drug conjugate (ADC). METxMET-ADC is a novel bispecific antibody that binds to two distinct epitopes on MET and is conjugated to a maytansinoid payload via a cleavable linker. The METxMET-ADC potently induces receptor internalization and mitotic arrest of cancer cells. Our in vitro studies show that the METxMET-ADC significantly and specifically decreases the viability of MET expressing uveal melanoma cell lines in a dose-dependent manner with an IC50 of less than 1 nM. A longer 7-day cell viability assay shows significantly enhanced inhibition of proliferation of several MET expressing cell lines (Mel270, Mel202, OMM1.3 and MP65) but not of OCM3 cells which express low levels of MET. Apoptosis is also induced up to 40% in the MET-expressing cell lines when treated with 10 nM of the METxMET-ADC for 48 hours. Cell cycle analysis shows a significant increase of OMM1.3 and Mel202 cells in mitosis after 6-24 hours of treatment and appearance of a sub-G1 population after 24-48 hours. Western blots confirm a decrease of MET protein levels, presumably due to receptor internalization and trafficking to lysosomes. Finally, treatment with the METxMET ADC is associated with induction of PARP cleavage and phosphorylation of histone H3 after 24 hours in OMM1.3 and Mel202 cells, but not in OCM3 cells. In summary, conjugation of a METxMET bispecific antibody with a cytotoxic payload allows for potent and selective killing of MET-expressing uveal melanoma cells. The METxMET-ADC demonstrates promising therapeutic potential for the treatment of uveal melanoma. Citation Format: Oliver Surriga, John DaSilva, Gary K. Schwartz. Preclinical evaluation of a novel MET antibody-drug conjugate in uveal melanoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 214.