Mutant calreticulin (CALR) (mutCALR)

Mutant calreticulin (mutCALR) is a key oncogenic driver in myeloproliferative neoplasms (MPNs), such as essential thrombocythemia and primary myelofibrosis. Mutations in exon 9 of the CALR gene result in a frameshift that replaces the acidic C-terminal domain with a novel, basic tail and causes the protein to lose its endoplasmic reticulum (ER) retention signal (KDEL). This mutant protein traffics to the cell surface, where it binds to and constitutively activates the thrombopoietin receptor (MPL), triggering the JAK-STAT signaling pathway. The "N-domain epitope" refers to a specific region within the globular N-terminal domain of the protein that becomes uniquely accessible or undergoes a conformational change in the mutant form, making it a selective target for immunotherapy. Therapeutic agents, such as the bispecific antibody INCA035784, are designed to recognize this N-domain epitope to distinguish mutant cells from those expressing wild-type calreticulin. By targeting these mutant-specific epitopes, drugs aim to disrupt the pathogenic CALR-MPL complex and induce the targeted elimination of malignant hematopoietic clones.

Other names

Mutant calreticulin N-domain epitopeCALR exon 9 mutantCALR neoantigenCALR neoepitopeCALRdel52 (Type 1 mutation)CALRins5 (Type 2 mutation)mutCALR

Therapeutic antibodies and bispecific T-cell engagers target mutant-specific epitopes (such as the N-domain conformational epitope or the C-terminal neo-epitope) to block the interaction between mutant CALR and the thrombopoietin receptor (MPL), thereby inhibiting constitutive JAK-STAT signaling and/or redirecting T-cells to selectively eliminate mutant-expressing cells.