Proteinase 3-derived peptide-MHC complex (PR3-pMHC)

Proteinase 3-derived peptide antigens presented on MHC molecules, specifically the PR1 peptide (VLQELNVTV) bound to HLA-A*02:01, serve as critical targets for immunotherapy in myeloid malignancies (Molldrem et al., 2000, Nature Medicine). Proteinase 3 (PR3) is a serine protease primarily found in the azurophilic granules of neutrophils, but it is aberrantly overexpressed in the cytoplasm and on the plasma membrane of leukemia blasts in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) (Rezvani et al., 2008, Blood). The presentation of PR3-derived peptides on the cell surface via MHC Class I molecules allows these malignant cells to be recognized by the adaptive immune system. Therapeutic strategies targeting this complex include PR1 peptide vaccines, TCR-engineered T cells, and TCR-like monoclonal antibodies such as h8F4, which are designed to induce selective lysis of leukemia cells (Sergeeva et al., 2016, Leukemia; Ma et al., 2016, Cancer Research). While these therapies leverage the overexpression of PR3 in cancer, the target is also present in normal mature neutrophils and is a known autoantigen in granulomatosis with polyangiitis (GPA). Consequently, therapeutic development must manage risks of neutropenia and the potential for inducing autoimmune vasculitis (Steiner et al., 2011, Journal of Clinical Oncology).

Other names

PR1-HLA-A2 complexProteinase 3 peptide-HLA complexPR1-MHC complexMyeloblastin-derived peptide-MHC complexPR3 epitope-MHC complex

Induction of T-cell mediated cytotoxicity or antibody-dependent cellular cytotoxicity (ADCC) against cells presenting Proteinase 3-derived peptides on MHC molecules.