PR1-specific T-cell receptor (PR1-TCR) (PR1-TCR)

The PR1-specific T-cell receptor (PR1-TCR) is a specialized immune receptor that recognizes the PR1 peptide, a nonameric epitope (VLQELNVTV) derived from the myeloid-associated serine proteases proteinase 3 (P3) and neutrophil elastase (NE) (Molldrem et al., 2000, Nature Medicine). This recognition occurs specifically when the PR1 peptide is presented by the Human Leukocyte Antigen (HLA)-A*02:01 MHC class I molecule. While P3 and NE are present in normal myeloid cells, they are aberrantly overexpressed in various hematologic malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS) (Rezvani et al., 2007, Blood). The PR1-TCR is a key component in the development of TCR-engineered T-cell therapies (TCR-T), where autologous or allogeneic T cells are modified to express this receptor to target and eliminate leukemic cells (Ma et al., 2016, Cancer Research). Binding of the PR1-TCR to the PR1-HLA-A*02:01 complex triggers T-cell activation, leading to the release of perforins and granzymes that induce apoptosis in the target malignant cell. Clinical utility of this receptor is primarily focused on treating HLA-A*02:01-positive patients with myeloid leukemia who have failed standard therapies (NCT02388321). A significant therapeutic challenge associated with this receptor is the potential for "on-target, off-tumor" toxicity, as the PR1 peptide is also presented on healthy mature neutrophils and myeloid progenitor cells, necessitating careful monitoring for neutropenia.

Other names

PR1/HLA-A*02:01-specific T-cell receptorVLQELNVTV-specific T-cell receptorProteinase 3-specific T-cell receptorNeutrophil elastase-specific T-cell receptorPR1-specific cytotoxic T-cell receptor recognizing PR1–HLA-A*0201 complex

The PR1-TCR binds to the PR1 peptide (VLQELNVTV) presented by the HLA-A*02:01 MHC class I molecule on the surface of target cells, initiating a signaling cascade through the CD3 complex that results in T-cell activation and the targeted lysis of the antigen-presenting cell.