Glycoprotein 100 (gp100) peptide–Human Leukocyte Antigen (HLA) class I complex (gp100-HLA complex)

The Glycoprotein 100 (gp100) peptide–Human Leukocyte Antigen (HLA) class I complex is a molecular assembly consisting of a peptide fragment derived from the gp100 protein (also known as PMEL17) presented on the cell surface by HLA class I molecules, most commonly HLA-A*02:01 [1.1.1, 1.3.1]. gp100 is a melanocyte-lineage specific protein involved in the biogenesis of melanosomes and is highly expressed in melanoma and uveal melanoma cells [1.3.1, 1.4.2]. This complex serves as a critical tumor-associated antigen (TAA) that allows the immune system to recognize and target malignant melanocytes while sparing most normal tissues, although it is also present on normal melanocytes [1.2.2, 1.5.1]. The complex is the primary target for tebentafusp, a first-in-class bispecific T-cell engager (ImmTAC) that utilizes an engineered high-affinity T-cell receptor (TCR) domain to recognize the gp100-HLA-A*02:01 complex [1.1.3, 1.2.1]. By simultaneously binding the target complex on tumor cells and the CD3 receptor on T-cells, tebentafusp redirects and activates the patient's own T-cells to induce tumor cell lysis [1.2.2, 1.2.5]. Because the recognition is HLA-restricted, clinical use of drugs targeting this complex requires patients to be positive for the specific HLA allele, such as HLA-A*02:01 [1.1.2, 1.1.4].

Other names

gp100 peptide–HLA class I complexgp100-HLA-A*02:01 complexPMEL peptide-MHC complexMelanocyte protein PMEL peptide-HLA complexGlycoprotein 100-HLA complexgp100-pHLA

Tebentafusp acts as a bispecific T-cell engager (ImmTAC) that redirects T-cells to tumor cells by simultaneously binding the gp100 peptide–HLA-A*02:01 complex via an engineered high-affinity T-cell receptor domain and the CD3 receptor on T-cells via an anti-CD3 single-chain variable fragment.