Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody

Denis Tvorogov, Chloe A.L. Thompson-Peach, Johannes Foßelteder, Mara Dottore, Frank Stomski, Suraiya A. Onnesha, Kelly Lim, Paul A.B. Moretti, Stuart M. Pitson, David M. Ross, Andreas Reinisch, Daniel Thomas, Angel F. Lopez

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Calreticulin (CALR) is recurrently mutated in myelofibrosis via a frameshift that removes an endoplasmic reticulum retention signal, creating a neoepitope potentially targetable by immunotherapeutic approaches. We developed a specific rat monoclonal IgG2α antibody, 4D7, directed against the common sequence encoded by both insertion and deletion mutations. 4D7 selectively bound to cells co-expressing mutant CALR and thrombopoietin receptor (TpoR) and blocked JAK-STAT signalling, TPO-independent proliferation and megakaryocyte differentiation of mutant CALR myelofibrosis progenitors by disrupting the binding of CALR dimers to TpoR. Importantly, 4D7 inhibited proliferation of patient samples with both insertion and deletion CALR mutations but not JAK2 V617F and prolonged survival in xenografted bone marrow models of mutant CALR-dependent myeloproliferation. Together, our data demonstrate a novel therapeutic approach to target a problematic disease driven by a recurrent somatic mutation that would normally be considered undruggable.

Original languageEnglish
Article numbere52904
JournalEMBO Reports
Volume23
Issue number4
DOIs
Publication statusPublished or Issued - 5 Apr 2022
Externally publishedYes

Keywords

  • calreticulin
  • monoclonal antibody
  • myelofibrosis
  • myeloproliferative neoplasm
  • stem cell progenitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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