Mutant calreticulin C-terminal neoepitope (Mutant CALR neoepitope)

Mutant calreticulin (CALR) C-terminal neoepitope is a tumor-specific antigen resulting from frameshift mutations in exon 9 of the CALR gene, which occur in approximately 25-35% of patients with essential thrombocythemia and primary myelofibrosis (Nangalia et al., 2013; Klampfl et al., 2013). These mutations generate a novel, positively charged C-terminal tail that lacks the wild-type KDEL endoplasmic reticulum retention signal, leading to the protein's translocation to the cell surface and its secretion (Araki et al., 2016). On the cell surface, the mutant CALR neoepitope physically interacts with the thrombopoietin receptor (MPL), triggering constitutive activation of the JAK-STAT signaling pathway and driving uncontrolled megakaryocyte proliferation (Chachoua et al., 2016; Elf et al., 2016). Because this neoepitope is entirely absent in healthy cells, it serves as an ideal therapeutic target for monoclonal antibodies and other immunotherapies (Tognon et al., 2023). Current drug development efforts, such as the monoclonal antibody INCA033989, focus on blocking the mutant CALR-MPL interaction or inducing immune-mediated destruction of the malignant clones (Reis et al., 2022).

Other names

CALR exon 9 mutantMutant CALR C-terminusCALR neoantigenCALR-mutMutant calreticulin

Monoclonal antibodies target the unique C-terminal neoepitope to block the interaction between mutant CALR and the thrombopoietin receptor (MPL), thereby inhibiting downstream JAK-STAT signaling and inducing antibody-dependent cellular cytotoxicity (ADCC) against malignant cells.