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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Tvorogov, D; Thompson-Peach, CAL; Foßelteder, J; Dottore, M; Stomski, F; Onnesha, SA; Lim, K; Moretti, PAB; Pitson, SM; Ross, DM; Reinisch, A; Thomas, D; Lopez, AF.
Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody.
EMBO Rep. 2022; 23(4):e52904
Doi: 10.15252/embr.202152904
[OPEN ACCESS]
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PubMed
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- Co-authors Med Uni Graz
- Foßelteder Johannes
- Reinisch Andreas
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Antibodies, Monoclonal - administration & dosage
- Calreticulin - genetics, metabolism
- Humans - administration & dosage
- Janus Kinase 2 - metabolism
- Mutation - administration & dosage
- Myeloproliferative Disorders - genetics, metabolism
- Rats - administration & dosage
- Find related publications in this database (Keywords)
- calreticulin
- monoclonal antibody
- myelofibrosis
- myeloproliferative neoplasm
- stem cell progenitor