Selective targeting of mutated calreticulin by the monoclonal antibody INCA033989 inhibits oncogenic function of MPN
Edimara S. Reis, Rebecca A. Buonpane, Hamza Celik, Caroline Marty, Angela Lei, Fatoumata Jobe, Mark Rupar, Yue Zhang, Darlise DiMatteo, Rahel Awdew, Bianca Lima Ferreira, Lynn Leffet, Lu Lu, Elodie Rosa, Maxime Evrard, Gaurang Trivedi, Brittney Wass, April Horsey, Xin He, Maryanne Covington, Alla Volgina, Florence Pasquier, Laurence Legros, Guillemette Fouquet, William Vainchenker, Yan‐ou Yang, Breann Barker, Jing Zhou, Shaun Stewart, Ian S. Hitchcock, Dashyant Dhanak, Ricardo Macarrón, Isabelle Plo, Horacio Nastri, Patrick A. Mayes
Abstract
ABSTRACT: Mutations in calreticulin (mutCALR) are the second most common drivers of myeloproliferative neoplasms (MPNs) and yet, the current therapeutic landscape lacks a selective agent for mutCALR-expressing MPNs. Here, we show that the monoclonal antibody INCA033989 selectively targets mutCALR-positive cells. INCA033989 antagonized mutCALR-driven signaling and proliferation in engineered cell lines and primary CD34+ cells from patients with MPN. No antibody binding or functional activity was observed in the cells lacking mutCALR. In a mouse model of mutCALR-driven MPN, treatment with an INCA033989 mouse surrogate antibody effectively prevented the development of thrombocytosis and accumulation of megakaryocytes in the bone marrow. INCA033989 reduced the pathogenic self-renewal of mutCALR-positive disease-initiating cells in both primary and secondary transplantations, illustrating its disease-modifying potential. In summary, we describe a novel mutCALR-targeted therapy for MPNs, a monoclonal antibody that selectively inhibits the oncogenic function of MPN cells without interfering with normal hematopoiesis.