Glycoprotein 100 peptide-HLA-A*02:01 complex (gp100-HLA-A2)

The Glycoprotein 100 (gp100) peptide-HLA-A*02:01 complex is a specific antigen-presenting structure found on the surface of melanocytes and melanoma cells. It consists of a 9-amino acid peptide (YLEPGPVTA) derived from the gp100 protein (also known as PMEL) presented by the Human Leukocyte Antigen (HLA) class I molecule A*02:01 (UniProt P17683; IEDB Epitope ID 71841). This complex is the primary therapeutic target for Tebentafusp, a first-in-class bispecific T-cell engager known as an ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) (FDA Label: Kimmtrak). Tebentafusp utilizes a high-affinity, engineered T-cell receptor (TCR) domain to recognize this specific peptide-MHC complex, while its anti-CD3 effector domain recruits and activates polyclonal T cells to eliminate the target cell (Nathan et al., 2021). Because gp100 is highly expressed in uveal and cutaneous melanoma, this complex serves as a critical target for redirecting the immune system against these malignancies (Damato et al., 2022). The biological function of this complex in a physiological context is to present intracellular antigens to the immune system for surveillance. In disease, its presence on tumor cells allows for the development of TCR-based therapies that can bypass the need for natural T-cell recognition. Clinical use of drugs targeting this complex requires patients to be HLA-A*02:01 positive, as the drug will not recognize gp100 peptides presented by other HLA types. Notable safety concerns include cytokine release syndrome and on-target off-tumor toxicities affecting normal melanocytes in the skin and eyes.

Other names

gp100-specific CD8+ T-cell receptor complexPMEL-HLA-A*02:01gp100(280-288) peptide-HLA-A*02:01Melanocyte protein PMEL peptide-MHC complexgp100-specific T-cell receptor target

Bispecific T-cell engager (ImmTAC) that binds the gp100 peptide-HLA complex on tumor cells and the CD3 receptor on T cells, leading to T-cell activation and tumor cell lysis.