Selective targeting of mutated calreticulin by the monoclonal antibody INCA033989 inhibits oncogenic function of MPN
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.
Authors
- Isabelle Plo (ORCID: https://orcid.org/0000-0002-5915-6910)
- Lynn Leffet
- Edimara S. Reis (ORCID: https://orcid.org/0000-0002-8438-275X)
- Breann Barker
- Rebecca A. Buonpane (ORCID: https://orcid.org/0000-0002-8158-8074)
- Fatoumata Jobe
- Shaun Stewart (ORCID: https://orcid.org/0000-0001-7915-9193)
- Gaurang Trivedi (ORCID: https://orcid.org/0000-0002-3410-2713)
- Dashyant Dhanak
- Guillemette Fouquet (ORCID: https://orcid.org/0000-0002-3751-393X)
- Darlise DiMatteo (ORCID: https://orcid.org/0000-0003-3440-3724)
- Patrick A. Mayes (ORCID: https://orcid.org/0000-0001-9104-4161)
- Ricardo Macarrón (ORCID: https://orcid.org/0000-0001-8868-2146)
- Elodie Rosa (ORCID: https://orcid.org/0009-0000-8543-6652)
- Yan‐ou Yang (ORCID: https://orcid.org/0009-0005-4869-9492)
- Bianca Lima Ferreira (ORCID: https://orcid.org/0000-0001-7578-2244)
- Ian S. Hitchcock (ORCID: https://orcid.org/0000-0001-7170-6703)
- Rahel Awdew
- Laurence Legros (ORCID: https://orcid.org/0000-0002-9567-7879)
- Alla Volgina
- Mark Rupar
- Caroline Marty (ORCID: https://orcid.org/0000-0003-4350-2302)
- Angela Lei
- William Vainchenker (ORCID: https://orcid.org/0000-0003-4705-202X)
- Horacio Nastri (ORCID: https://orcid.org/0000-0002-0025-5930)
- April Horsey
- Brittney Wass
- Yue Zhang (ORCID: https://orcid.org/0000-0003-4597-9964)
- Xin He (ORCID: https://orcid.org/0000-0003-1677-5954)
- Jing Zhou (ORCID: https://orcid.org/0009-0007-1644-1694)
- Florence Pasquier (ORCID: https://orcid.org/0000-0003-1432-5300)
- Hamza Celik
- Lu Lu (ORCID: https://orcid.org/0000-0002-0960-1529)
- Maryanne Covington
- Maxime Evrard
Institutions
- Inserm (FR)
- Wilmington University (US)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Centre Hospitalier Sud Francilien (FR)
- Science City York (United Kingdom) (GB)
- Bicêtre Hospital (FR)
- University of York (GB)
- Incyte (United States) (US)
Publication Details
- Journal
- Blood
- Published
- 2024-09-10
- DOI
- https://doi.org/10.1182/blood.2024024373
- Citations
- 23
- Primary Topic
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 10.07
Funders
- Incyte
- Institut National de la Santé et de la Recherche Médicale