Human leukocyte antigen A*02:01 (HLA-A*02:01)-glycoprotein 100 (gp100) peptide-major histocompatibility complex (MHC) class I complex (HLA-A*02:01/gp100 pMHC)

The Human leukocyte antigen A*02:01 (HLA-A*02:01)-glycoprotein 100 (gp100) peptide-major histocompatibility complex (MHC) class I complex is a molecular assembly comprising the HLA-A*02:01 allele and a processed peptide fragment derived from the gp100 (PMEL) protein [UniProt P17683]. This complex is presented on the surface of melanocytes and melanoma cells, where it serves as a specific ligand for T-cell receptors (TCRs) to trigger an immune response [PubMed: 34614324]. In clinical oncology, this pMHC complex is a validated therapeutic target for uveal and cutaneous melanoma, diseases where gp100 is frequently overexpressed [FDA: Kimmtrak Label]. The drug tebentafusp is a first-in-class bispecific T-cell engager (ImmTAC) designed to bind this specific complex with high affinity while simultaneously engaging the CD3 receptor on T-cells [NEJM: 385:1196-1206]. This interaction facilitates the formation of an artificial immunological synapse, leading to the targeted lysis of melanoma cells by redirected T-cells [Nature Medicine: 23, 1417–1423]. Because gp100 is also expressed in normal melanocytes, therapeutic targeting can lead to on-target, off-tumor effects such as vitiligo or skin rashes [EMA: Kimmtrak Assessment Report]. Patient eligibility for such therapies is strictly dependent on the presence of the HLA-A*02:01 allele as a mandatory biomarker [ClinicalTrials.gov: NCT03070392].

Other names

HLA-A*02:01-PMEL complexgp100:HLA-A2 complexgp100(280-288)/HLA-A*02:01gp100 peptide-HLA-A*02:01 complexPMEL-derived peptide-MHC complex

Bispecific T-cell engager (ImmTAC) that binds the pMHC complex and CD3 to redirect T-cell cytotoxicity.