Selective targeting of mutated calreticulin by the monoclonal antibody INCA033989 inhibits oncogenic function of MPN

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• Calreticulin mutations (mutCALR) are key drivers in myeloproliferative neoplasms (MPNs).
• Existing treatments for mutCALR-positive MPNs lack targeted specificity.
• There is a critical need for selective therapies against mutCALR-driven MPNs.

Purpose of the Study:

• To evaluate the efficacy of the monoclonal antibody INCA033989 as a targeted therapy for mutCALR-positive MPNs.
• To assess the selectivity of INCA033989 against cells with and without mutCALR.
• To investigate the disease-modifying potential of INCA033989 in preclinical models.

Main Methods:

• Testing INCA033989 binding and functional activity in engineered cell lines and primary patient cells.
• Evaluating INCA033989's effect on signaling and proliferation in mutCALR-positive cells.
• Assessing INCA033989's efficacy in a mouse model of mutCALR-driven MPN, including transplantation studies.

Main Results:

• INCA033989 demonstrated selective targeting and inhibition of mutCALR-positive cells.
• The antibody effectively antagonized mutCALR-driven signaling and proliferation.
• In vivo studies showed prevention of thrombocytosis and megakaryocyte accumulation, and reduced disease-initiating cell self-renewal.
• No adverse effects on normal hematopoiesis were observed.

Conclusions:

• INCA033989 represents a novel, selective therapeutic agent for mutCALR-positive MPNs.
• The antibody targets the oncogenic function of mutCALR, offering disease-modifying potential.
• INCA033989 warrants further investigation as a treatment for MPNs driven by calreticulin mutations.