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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 substantially improved the treatment of melanoma. However, therapeutic strategies are still needed for unresponsive or treatment-relapsed patients with melanoma. To discover antibody-drug conjugate (ADC)-tractable cell surface targets for melanoma, we developed an atlas of melanoma cell surface-binding antibodies (pAb) using a proteome-scale antibody array platform. 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 with 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 antiangiogenic 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.
Significance:
Discovery of melanoma-targeting antibodies using a proteome-scale array and use of a cutting-edge linker-payload system led to development of a MUC18-targeting antibody-exatecan conjugate with clinical potential for treating major melanoma subtypes.
Insights
Researchers identified MUC18 as a promising target for antibody-drug conjugates (ADCs) in melanoma treatment. An MUC18-targeted ADC, AMT-253, demonstrated potent anti-tumor activity and potential for various solid tumors.
Area of Science:
- Oncology
- Immunology
- Drug Development
Background:
- Melanoma treatment advances with targeted therapy and immunotherapy, yet challenges remain for unresponsive or relapsed patients.
- New therapeutic strategies are crucial for overcoming treatment resistance in melanoma.
Purpose of the Study:
- To discover novel antibody-drug conjugate (ADC)-tractable cell surface targets for melanoma.
- To develop and evaluate MUC18-targeting ADCs for melanoma and other solid tumors.
Main Methods:
- Developed a proteome-scale antibody array to identify melanoma cell surface-binding antibodies.
- Engineered MUC18-directed ADCs, including AMT-253 with exatecan payload.
- Evaluated ADC efficacy in melanoma cell lines, patient-derived xenografts, and preclinical models.
Main Results:
- Identified MUC18 as a highly expressed target on melanoma cells and tumor vasculature.
- AMT-253 demonstrated potent MUC18-specific cytotoxicity, bystander killing, and favorable pharmacokinetics in non-human primates.
- MUC18-targeting ADCs showed significant antitumor activity in preclinical models, including combination therapy and efficacy in other solid tumors.
Conclusions:
- MUC18 is a promising dual-compartment target for melanoma therapy.
- AMT-253 exhibits strong therapeutic potential for melanoma and other MUC18-expressing solid tumors.
- The target/antibody discovery platform and linker-payload system facilitate the development of novel ADCs for cancer treatment.
