anti-mutant calreticulin monoclonal antibody INCA033989

A human immunoglobulin G1 (IgG1) monoclonal antibody targeting the mutated form of calreticulin (mutCALR), with potential antineoplastic activity. Upon administration, anti-mutCALR monoclonal antibody INCA033989 selectively targets and binds to mutCALR expressed on CALR mutated CD34-positive hematopoietic stem cells (HSCs) while not binding to normal wild-type (WT) CALR on healthy CD34-positive HSCs. This prevents the formation of a mutCALR complex with the thrombopoietin receptor (TPO-R) in the endoplasmic reticulum (ER), prevents the CALR mutant-dependent TPO-R dimerization and suppresses TPO-R signaling. This prevents the activation of the downstream Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling pathway. This prevents mutCALR-driven oncogenic cell proliferation, causes cell cycle arrest and induces cell death. CALR mutations, either insertions or deletions in exon 9, result in a frameshift that causes the loss of the KDEL ER retention motif. CALR mutations drive a variety of myeloproliferative neoplasms (MPNs).