Melanocyte protein PMEL (gp100) peptide-HLA-A*02:01 complex (gp100/HLA-A*02:01)

The target is a specific peptide-major histocompatibility complex (pMHC) consisting of fragments from the Melanocyte protein PMEL (gp100) bound to the HLA-A*02:01 molecule. gp100 is a lineage-specific protein essential for the maturation of melanosomes, the organelles where melanin is synthesized (UniProt: P40967). While expressed in normal melanocytes, gp100 is highly overexpressed in cutaneous and uveal melanoma, making its HLA-presented peptides attractive targets for T-cell based therapies (PubMed: 10359807). The most prominent drug targeting this complex is Tebentafusp, a bispecific T-cell engager that uses a high-affinity TCR to recognize the gp100 peptide-HLA-A*02:01 complex and an anti-CD3 domain to activate T cells (NEJM: 385:1196-1206). Because the target is also present on healthy melanocytes in the skin, eye, and inner ear, therapy is often associated with on-target off-tumor toxicities such as rash and vitiligo. Clinical efficacy is strictly dependent on the patient's HLA genotype, specifically requiring the HLA-A*02:01 allele for drug binding and activity (PubMed: 35303746).

Other names

gp100PMEL17Silver locus protein homologMelanocyte-specific lineage antigen gp100ME20-Mgp100-HLA-A2 complexPMEL

T-cell redirection via a bispecific fusion protein (ImmTAC) that binds the peptide-MHC complex with high affinity and recruits T cells via a CD3-binding domain (PubMed: 34551229).