Work

Selective targeting of mutated calreticulin by the monoclonal antibody INCA033989 inhibits oncogenic function of MPN

Year: 2024

Type: article

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.

Source: White Rose Research Online (University of Leeds, The University of Sheffield, University of York)

Author: Hitchcock, Ian Stuart

Institution: University of York

Language: English

Topic: Myeloproliferative Neoplasms: Diagnosis and Treatment

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Incyte, Institut National de la Santé et de la Recherche Médicale

OpenAlex ID: W7080352349