Tebentafusp

Glycoprotein 100 (gp100) is a transmembrane glycoprotein highly expressed in melanoma cells and weakly expressed by normal melanocytes or other tissues. Gp100 is presented as a human leukocyte antigen (HLA)-peptide complex on the cell surface. Gp100 has a particularly high affinity for the HLA-A subtype HLA-A*02:01. HLAs are part of a protein complex that normally regulates immune function: natural T cell responses are initiated by the interaction between the T-cell receptor (TCR) and its peptide antigen, such as gp100, presented by HLA on the surface of a target cell.

Tebentafusp is a bispecific gp100 peptide-HLA-A*02:01 directed T cell receptor CD3 T cell engager. It consists of a TCR targeting domain - or a TCR arm - fused to a single-chain variable fragment (scFv) anti-CD3 effector domain. The TCR arm binds to a gp100 peptide bound to HLA-A on the uveal melanoma tumour cell surface. The anti-CD3 effector domain of tebentafusp engages and activates CD3+ T cells to inflammatory cytokines and cytolytic proteins, which results in direct lysis of uveal melanoma tumour cells. The anti-CD3 fragment of the drug has a lower affinity, so the T cells are not stimulated unless tebentafusp has detected gp100.

Tebentafusp is only effective in HLA-A*02:01-positive patients.