The advent of BRAF inhibitors and immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of melanoma patients. However, melanoma subtypes such as limbal, mucosal, and uveal melanomas are less responsive to these therapies than cutaneous melanomas, and new therapeutic agents are urgently needed for treatment-resistant patients. Antibody-drug conjugates (ADCs) achieve targeted killing of tumor cells by covalently linking cytotoxic small molecules to antibodies targeting antigens on the surface of tumor cells. In recent years, ADC drugs have made remarkable progress in solid tumors such as breast cancer, gastric cancer, uroepithelial cancer, cervical cancer, and ovarian cancer. However, no ADC drugs have been successful in melanoma.

Recently, researchers published an article in Cancer Research entitled A cell surface-binding antibody atlas nominates a MUC18-directed antibody-drug conjugate for targeting melanoma. The study screened and developed a potential first-in-class ADC drug targeting MUC18, AMT-253, which has shown significant anti-tumor activity in major subtypes of melanoma as well as in a variety of other solid tumors.

The study first utilized the antibody microarray platform (PETAL) to screen for targets such as LGR6, TRPM1, ASAP1, and MUC18, which are highly expressed in melanoma cells. Among them, MUC18 was highly expressed in various subtypes of melanoma as well as tumor vasculature.

The antitumor efficacy and safety of two different types of ADCs based on vc-MMAE (AMT-253-M) and T1000-exatecan (AMT-253), a proprietary ADC platform of Puzo Discovery Pharmaceuticals, Inc., were comparatively evaluated against MUC18. AMT-253 showed a higher therapeutic window than AMT-253-M and was selected as a candidate for further investigation. was selected as a candidate molecule for further study and evaluation.

In the mucosal melanoma GAK CDX model, the alternative ADC molecule Ab15A-T1000-exatecan, which recognizes only mouse MUC18, was specifically localized to the tumor blood vessels and was able to significantly inhibit tumor growth, demonstrating that the MUC18 ADC has the effect of targeting the tumor blood vessels. This result suggests that it is possible for AMT-253 to achieve simultaneous targeting of tumor cells as well as tumor blood vessels in the clinic, thus experimenting with a dual tumor inhibition effect.

Previous clinical trials observed that PD-1/L1 antibodies and VEGF pathway inhibitors showed a combination effect in mucosal melanoma patients. Thus, the effect of AMT-253 in combination with the anti-angiogenic Bevacizumab was investigated in the GAK model. The results showed that both AMT-253 and Bevacizumab inhibited tumor growth, and the combination of the two showed a stronger tumor-suppressive effect. This result supports the exploration of combinations during clinical development in the future.

Considering that MUC18 is also widely expressed in a variety of other solid tumors, the article concludes by exploring the antitumor activity of AMT-253 in a variety of solid tumor models other than melanoma. AMT-253 significantly inhibited tumor growth in a variety of CDX or PDX models, such as cervical squamous carcinoma, head and neck squamous carcinoma, esophageal squamous carcinoma, lung squamous carcinoma, small-cell lung carcinoma, ovarian carcinoma, and hepatocellular carcinoma. It shows the promise of AMT-253 application in these solid tumors.