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Study Reveals AMT-253 as a Potential First-in-Class ADC for Targeting Melanoma and Solid Tumors

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.

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.

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