Melanocyte protein PMEL (gp100) modified epitope (209-217) (gp100:209-217(210M))

Melanocyte protein PMEL (gp100) is a transmembrane glycoprotein primarily expressed in melanocytes and overexpressed in most melanomas (UniProt P40967). The gp100:209–217 epitope is a specific peptide fragment (ITDQVPFSV) that is processed and presented on the cell surface by the HLA-A*02:01 molecule. To improve therapeutic efficacy, a modified version of this epitope (g209-2M or IMDQVPFSV) was engineered with a threonine-to-methionine substitution at the second position to increase its binding affinity to HLA-A*02:01 (PubMed: 10446860). This modified epitope serves as the target for tebentafusp, the first-in-class bispecific T-cell receptor (TCR) fusion protein approved for uveal melanoma (FDA, 2022). Tebentafusp works by binding the gp100:209-217(210M) peptide-HLA complex on tumor cells and the CD3 receptor on T cells, thereby inducing T-cell mediated lysis of the cancer cells. Clinical use of therapies targeting this epitope requires patients to be HLA-A*02:01 positive, making it a critical biomarker for patient selection. Because gp100 is also expressed in normal melanocytes, common side effects include skin-related toxicities such as rash, pruritus, and vitiligo.

Other names

PMELPMEL17Melanoma-associated antigen gp100g209-2MIMDQVPFSVgp100:209-217

T-cell redirection via bispecific T-cell receptor (TCR) fusion protein or active immunization to induce tumor-specific cytotoxic T-lymphocyte response.