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
  • 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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