Glycoprotein 100 peptide–Human Leukocyte Antigen-A*02:01 complex (gp100-HLA-A*02:01) (gp100-HLA-A*02:01)

The Glycoprotein 100 peptide–Human Leukocyte Antigen-A*02:01 complex (gp100-HLA-A*02:01) is a molecular assembly consisting of a peptide fragment derived from the premelanosome protein (PMEL, also known as gp100) presented on the cell surface by the Major Histocompatibility Complex (MHC) class I molecule HLA-A*02:01 [1, 2]. PMEL is a type I transmembrane glycoprotein essential for the structural organization of premelanosomes and melanin synthesis in melanocytes [4, 13]. While expressed in normal pigment-producing cells, gp100 is significantly overexpressed in malignant melanomas, including uveal and cutaneous subtypes, making its MHC-presented peptides ideal tumor-associated antigens [5, 7]. This specific peptide-MHC (pMHC) complex is the primary target for tebentafusp, a first-in-class bispecific T-cell receptor (TCR) fusion protein that redirects T cells to kill melanoma cells [3, 6]. By binding the gp100-pMHC complex with high affinity and simultaneously engaging the CD3 receptor on T cells, these therapies bypass the need for natural TCR recognition and overcome tumor immune evasion [1, 10, 12]. Clinical use of drugs targeting this complex has demonstrated significant survival benefits in metastatic uveal melanoma, a disease historically resistant to conventional immunotherapies [11]. However, because gp100 is also expressed in normal melanocytes, treatment often results in on-target, off-tumor toxicities such as skin rash and pruritus [2, 8]. Monitoring for cytokine release syndrome is also critical during the initial phases of treatment due to the potent T-cell activation induced by these agents [9, 11].

Other names

gp100/PMEL-specific peptide–MHC complexPMEL peptide–HLA-A*02:01 complexgp100-pMHCPMEL-pMHCgp100/HLA-A2 complexGlycoprotein 100-pMHCPremelanosome protein-pMHCgp100 peptide–MHC complex

Bispecific T-cell redirection and activation via TCR-CD3 engagement.