A Cell Surface-Binding Antibody Atlas Nominates a MUC18-Directed Antibody–Drug Conjugate for Targeting Melanoma

Abstract

Recent advances in targeted therapy and immunotherapy have damage and apoptosis and a strong bystander killing effect, substantially improved the treatment of melanoma. However, leading to potent antitumor activities against melanoma cell line therapeutic strategies are still needed for unresponsive or treat- and patient-derived xenograft models. Tumor vasculature targetment-relapsed patients with melanoma. To discover antibody–ing by a mouse MUC18-specific antibody–T1000-exatecan con-drug conjugate (ADC)–tractable cell surface targets for melanojugate inhibited tumor growth in human melanoma xenografts. ma, we developed an atlas of melanoma cell surface–binding Combination therapy of AMT-253 with an antiangiogenic agent antibodies (pAb) using a proteome-scale antibody array plat-generated higher efficacy than single agent in a mucosal melaform. Target identification of pAbs led to development of melnoma model. Beyond melanoma, AMT-253 was also efficacious anoma cell killing ADCs against LGR6, TRPM1, ASAP1, and in a wide range of MUC18-expressing solid tumors. Efficient MUC18, among others. MUC18 was overexpressed in both target/antibody discovery in combination with the T moiety–tumor cells and tumor-infiltrating blood vessels across major exatecan linker–payload exemplified here may facilitate discovmelanoma subtypes, making it a potential dual-compartment ery of new ADC to improve cancer treatment. and universal melanoma therapeutic target. AMT-253, an MUC18-directed ADC based on topoisomerase I inhibitor exaSignificance: Discovery of melanoma-targeting antibodies using tecan and a self-immolative T moiety, had a higher therapeutic a proteome-scale array and use of a cutting-edge linker–payload index compared with its microtubule inhibitor–based counter-system led to development of a MUC18-targeting antibody–part and favorable pharmacokinetics and tolerability in monkeys. exatecan conjugate with clinical potential for treating major melAMT-253 exhibited MUC18-specific cytotoxicity through DNA anoma subtypes.