Malignant Melanoma (MM) is an aggressive disease of melanocytes, characterized by high metastatic potential and mortality rate. Although recent immunotherapies and targeted agents have improved outcome, there remains a pressing need for additional therapeutic strategies. Bispecific T-cell Engagers (BTCEs) have recently emerged as a promising approach to harness the immune system by directing T cells specifically against tumor cells, gaining increasing relevance in the evolving therapeutic landscape. UMG1 is a unique epitope of CD43 that differs from the molecule’s canonical expression profile. While CD43 is broadly expressed across many cell types, thus limiting its suitability for targeted interventions, the UMG1 epitope is notably restricted to cortical thymocytes and a small subset of peripheral T lymphocytes, becoming prominent only when CD43 is aberrantly expressed in malignancies. This distinctive pattern makes UMG1 an appealing immunotherapeutic target. Previous studies have demonstrated potent antitumor activity of UMG1/CD3ε-BTCE in hematologic malignancies, prompting further investigation of UMG1 as a tumor-specific target in MM.

UMG1 reactivity was assessed by immunohistochemistry on Tissue Microarrays (TMAs) and pathology slides from MM specimens. Immunofluorescence was performed on primary and metastatic MM cell lines to confirm UMG1 expression. UMG1-positive MM cells were co-cultured with healthy donor-derived Peripheral Blood Mononuclear Cells (PBMCs) in the presence of escalating concentrations of UMG1/CD3ε-BTCE for 72 hours. Cytotoxicity was measured via tumor cell viability, and T-cell activation was evaluated using markers CD69, CD25, and CD107a.

Approximately 50% of MM samples showed variable membrane staining for UMG1, while normal skin tissues were negative. Immunofluorescence confirmed these findings in both primary and metastatic MM cell lines, underscoring UMG1's role as a MM-specific marker. UMG1/CD3ε-BTCE induced a robust, dose-dependent T cell-mediated cytotoxic response against UMG1-positive MM cells. This response occurred together with significant upregulation of CD69 and CD25, and enhanced CD107a expression on CD8⁺ T cells, reflecting effective T-cell activation and degranulation. These results indicate that targeting the UMG1 epitope effectively engages T cells to eliminate MM cells.

UMG1 is a novel promising therapeutic target in MM due to its distinct, tumor-specific expression. UMG1/CD3ε-BTCE elicits potent T cell responses and significant cytotoxicity, offering a novel immunotherapeutic approach. These findings support in vivo investigations to validate the translational potential of UMG1-targeted therapy against MM.