A fully human IgG1 antibody that selectively binds to mutant CALR, INCA033989 demonstrated activity in cells from MPN patients and a mouse model of essential thrombocythemia. In the model, INCA033989 selectively decreased levels of mutant CALR-positive platelets, re-established normal megakaryopoiesis, and selectively targeted mutant CALR disease-initiating clones.