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New Antibody-Drug Conjugate AMT-253 Demonstrates Dual Tumor Inhibition in Melanoma

The introduction of BRAF inhibitors and immune checkpoint inhibitors (ICIs) has substantially improved outcomes for melanoma patients. However, certain melanoma subtypes—such as limbal, mucosal, and uveal melanomas—are less responsive to these therapies compared to cutaneous melanoma, highlighting the urgent need for new treatments for therapy-resistant patients. One promising approach is antibody-drug conjugates (ADCs), which target and destroy tumor cells by attaching cytotoxic small molecules to antibodies that bind to tumor cell surface antigens. While ADCs have made significant strides in treating solid tumors like breast cancer, gastric cancer, uroepithelial cancer, cervical cancer, and ovarian cancer, their application in melanoma has yet to yield success.

A recent study published in Cancer Research titled A Cell Surface-Binding Antibody Atlas Nominates a MUC18-Directed antibody-drug conjugate for targeting melanoma  presents promising new research on ADCs for melanoma treatment. The study describes the development of AMT-253, a potential first-in-class ADC targeting MUC18, which has demonstrated significant antitumor activity across major melanoma subtypes and other solid tumors.

Using a cutting-edge antibody microarray platform (PETAL), the researchers screened for antigens highly expressed on melanoma cells, including LGR6, TRPM1, ASAP1, and MUC18. Among these, MUC18 stood out for its high expression not only in melanoma but also in tumor vasculature, making it an ideal target for ADC therapy.

The team evaluated the antitumor efficacy and safety of two different ADC formulations: AMT-253-M, based on the cytotoxic agent vc-MMAE, and AMT-253, which uses T1000-exatecan, a proprietary ADC platform developed by Puzo Discovery Pharmaceuticals. AMT-253 demonstrated a wider therapeutic window than AMT-253-M, making it the candidate for further clinical investigation.

In the mucosal melanoma GAK CDX model, a modified ADC (Ab15A-T1000-exatecan), designed to target only mouse MUC18, was localized to tumor blood vessels and significantly inhibited tumor growth. This finding suggests that AMT-253 could potentially target both tumor cells and tumor blood vessels in clinical settings, providing a dual mechanism of tumor inhibition.

Given that PD-1/L1 inhibitors and VEGF pathway inhibitors have previously shown synergy in mucosal melanoma patients, the study also explored the combination of AMT-253 with the anti-angiogenic drug Bevacizumab in the GAK model. The combination of AMT-253 and Bevacizumab resulted in a stronger tumor-suppressive effect compared to either treatment alone, suggesting that this combination approach warrants further investigation in clinical trials.

Finally, the study assessed the potential of AMT-253 in treating other solid tumors, given that MUC18 is widely expressed across various cancer types. In preclinical models of cervical squamous carcinoma, head and neck squamous carcinoma, esophageal squamous carcinoma, lung squamous carcinoma, small-cell lung carcinoma, ovarian carcinoma, and hepatocellular carcinoma, AMT-253 significantly inhibited tumor growth. These results suggest that AMT-253 has promising therapeutic potential beyond melanoma, with broad applicability for a variety of solid tumors.