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SOHO 2025 | Targeting CALR mutations in MPNs: a promising novel immunotherapeutic approach
John Mascarenhas, MD, Icahn School of Medicine at Mount Sinai, New York, NY, discusses the therapeutic approach of targeting CALR mutations in patients with myeloproliferative neoplasms (MPNs), sharing his excitement for this novel approach. He also highlights promising Phase I data observed with INCA033989. This interview took place at the 13th Annual Meeting of the Society of Hematologic Oncology (SOHO 2025) in Houston, TX.
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Transcript
So the CALR mutation aspect I think has been in some ways somewhat unexpected molecularly defined therapeutic approach that I think is very cool and very exciting. So we know that the mutant CALR protein is aberrantly expressed on the surface of MPN cells in collaboration in conjunction with the MPL receptor, that’s the thrombopoietin receptor, and that if you target that complex with an antibody like the Incyte INCA3989 molecule, you actually bind, very specifically and selectively and intensely, you bind that complex, internalize it through endocytosis, and turn off the aberrant JAK-STAT signaling pathway in that cell...
So the CALR mutation aspect I think has been in some ways somewhat unexpected molecularly defined therapeutic approach that I think is very cool and very exciting. So we know that the mutant CALR protein is aberrantly expressed on the surface of MPN cells in collaboration in conjunction with the MPL receptor, that’s the thrombopoietin receptor, and that if you target that complex with an antibody like the Incyte INCA3989 molecule, you actually bind, very specifically and selectively and intensely, you bind that complex, internalize it through endocytosis, and turn off the aberrant JAK-STAT signaling pathway in that cell. And laboratory studies would tell us that that would lead to cell death in that very select group of cells that express that protein. So it’s a really nice immunologic approach to treating CALR mutant disease that doesn’t actually engage the immune system. So it’s got a silent Fc portion. So you’re not incurring an immune response, but you’re using an immune therapy to target the diseased cells. And we showed data at EHA 2025 in Milan of Phase I data in a dose escalation, which is now expanding in an expansion phase of the activity of this mutant CALR antibody and importantly, the safety in phase one. Very safe, no dose-limiting toxicity, and we saw profound platelet normalization. And I don’t mean lowering of the platelets, I mean normalization of the platelets, particularly as we amp the dose. We saw some differences between type 1 and type 2, so we’re learning about biology even more so with these treatments. But I am very optimistic and enthusiastic that therapies like this CALR antibody, and there are therapies that are building on this, so bispecifics, maybe even CAR-Ts, are likely to carve out a niche in the disease say where we’re treating patients based on mutation perhaps and not just based on a diagnosis.
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