Data for: A cell surface-binding antibody atlas nominates a MUC18-directed antibody-drug conjugate for targeting melanoma

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