Human leukocyte antigen A*02:01–gp100 peptide (209-217, 2M variant) complex (HLA-A*02:01–gp100(2M))

The Human leukocyte antigen A*02:01–gp100 peptide (209-217, 2M variant) complex is a specific peptide-major histocompatibility complex (pMHC) target found on the surface of melanocytes and melanoma cells (Nathan et al., 2021, NEJM). It consists of the HLA-A*02:01 molecule presenting a modified 9-amino acid fragment (IMDQVPFSV) derived from the gp100 (PMEL) protein, which is a lineage-specific antigen involved in melanosome formation (Parkhurst et al., 1996, J Immunol). The 2M variant involves a threonine-to-methionine substitution at the second position of the peptide, which significantly enhances its binding affinity to the HLA-A*02:01 groove compared to the wild-type peptide (PMID: 8754852). This complex serves as a highly specific marker for melanoma, particularly uveal melanoma, where gp100 is consistently overexpressed. Therapeutic strategies, such as the bispecific protein tebentafusp, utilize a high-affinity T-cell receptor (TCR) domain to recognize this pMHC complex and an anti-CD3 domain to recruit and activate cytotoxic T-cells (Middleton et al., 2020, Clin Cancer Res). By bypassing the need for natural TCR recognition, these drugs induce a potent immune response against tumor cells in patients who are HLA-A*02:01 positive. However, because gp100 is also expressed in normal melanocytes in the skin and eye, treatment can lead to off-tumor, on-target toxicities such as rash, pruritus, and edema (Kimmtrak FDA Label). This target represents a milestone in TCR-based therapeutics, being the first pMHC complex successfully targeted by an approved bispecific T-cell engager.

Other names

HLA-A*02:01-gp100(209-217)2Mgp100:209-217(2M)-HLA-A*02:01 complexMelanocyte protein PMEL peptide-MHC complexHLA-A2-gp100

Bispecific T-cell engager (ImmTAC) that redirects T-cells to kill gp100-expressing cells by binding the HLA-peptide complex via a high-affinity TCR domain and CD3 via an anti-CD3 scFv domain.