2. Academic Validation
  3. Selective targeting of mutated calreticulin by the monoclonal antibody INCA033989 inhibits oncogenic function of MPN

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

  • Blood. 2024 Nov 28;144(22):2336-2348. doi: 10.1182/blood.2024024373.
Edimara S Reis 1,  Rebecca Buonpane 1,  Hamza Celik 1,  Caroline Marty 2 3 4,  Angela Lei 1,  Fatoumata Jobe 1,  Mark Rupar 1,  Yue Zhang 1,  Darlise DiMatteo 1,  Rahel Awdew 1,  Bianca L Ferreira 5,  Lynn Leffet 1,  Lu Lu 1,  Elodie Rosa 2 3 4,  Maxime Evrard 2 3 4,  Gaurang Trivedi 1,  Brittney Wass 1,  April Horsey 1,  Xin He 1,  Maryanne Covington 1,  Alla Volgina 1,  Florence Pasquier 2 3 4 6,  Laurence Legros 7,  Guillemette Fouquet 8,  William Vainchenker 2 3 4,  Yan-Ou Yang 1,  Breann Barker 1,  Jing Zhou 1,  Shaun Stewart 1,  Ian S Hitchcock 5,  Dashyant Dhanak 1,  Ricardo Macarron 1,  Isabelle Plo 2 3 4,  Horacio Nastri 1,  Patrick A Mayes 1
Affiliations

Affiliations

  • 1 Incyte Research Institute, Wilmington, DE.
  • 2 INSERM U1287 Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • 3 Gustave Roussy, Villejuif, France.
  • 4 Université Paris-Saclay, Villejuif, France.
  • 5 Department of Biology, York Biomedical Research Institute, University of York, York, United Kingdom.
  • 6 Hematology Department, Gustave Roussy, Villejuif, France.
  • 7 Clinical Hematology Department, APHP-Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
  • 8 Clinical Hematology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France.
PMID: 39255409 DOI: 10.1182/blood.2024024373
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.

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