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INCA033989 is an antibody that recognises only the mutant form of calreticulin found in about a quarter of essential thrombocythaemia and myelofibrosis patients. Unlike existing drugs, which control counts, it targets the diseased clone itself and is in first-in-human trials.
INCA033989 is Incyte's antibody against mutant calreticulin (CALR). CALR frameshift mutations are the second commonest driver of essential thrombocythaemia and primary myelofibrosis after JAK2 V617F; the mutant protein gains a positively charged tail that lets it bind and activate the thrombopoietin receptor MPL from outside the cell, an accessible target absent from normal cells. In preclinical work the antibody blocked mutant-CALR signalling and selectively suppressed the clone.
A phase 1 trial in essential thrombocythaemia and myelofibrosis began in 2024, with early reports of platelet normalisation and falls in mutant-allele burden in essential thrombocythaemia. The essential thrombocythaemia page names it among the first treatments that target the clone rather than the counts.
Binds the novel C-terminal tail that frameshift mutations give calreticulin, which the mutant protein uses to dimerise and activate the thrombopoietin receptor MPL on the cell surface; blocking it switches off JAK-STAT signalling only in the mutant clone. Connects to JAK2.
1.INCA033989 binds JAK2.
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Query for this drug: (TITLE:"INCA033989" OR ABSTRACT:"INCA033989" OR TITLE:"INCA-033989" OR ABSTRACT:"INCA-033989" OR TITLE:"Mutant-CALR antibody" OR ABSTRACT:"Mutant-CALR antibody") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about INCA033989, not a curated reading list.
Shares Monoclonal antibodies and the tag subtype-drugs-wave.
Shares Monoclonal antibodies and the tag subtype-drugs-wave.
Shares Essential thrombocythaemia (ET), JAK2, Ruxolitinib.
Shares Ruxolitinib, Incyte.
Shares Ruxolitinib, Incyte.