INCA035784 a novel, T-cell-redirecting antibody for CALR mutations in MPN

While targeted treatments such as Janus kinase (JAK) inhibitors have significantly advanced the treatment of myeloproliferative neoplasms (MPN), they do not eliminate the mutant cell population in MPN. Mutations in CALR (mutCALR) result in cell surface translocation of the mutCALR-TpoR complex, resulting in JAK/STAT pathway activation, making it an ideal candidate for developing therapeutic options. INCA035784 is a novel equipotent T-cell-redirecting antibody with potential to recognize and eliminate mutCALR cells. During the European Hematology Association (EHA) 2025 Congress, June 12–15, 2025, Milan, IT, Beth Psaila discussed the effects of INCA035784 on mutCALR.

The specific binding domain of INCA035784 was determined by cryo-electron microscopy. Cell surface binding was confirmed using isogenic cell lines expressing type 1 and 2 mutCALR and healthy donor (HD) T cells. T-cell-mediated cytotoxicity was determined using co-cultures of isogenic cells and patient-derived CD34+ mutCALR+ cells with HD T cells. INCA035784-mediated cytokine induction was determined using HD peripheral blood mononuclear cells (PBMCs), HD T cells, and patient-derived PBMCs.

Key learnings

As the N-domain is conserved across all types of C-terminus mutCALR, INCA035784 exhibited equipotent binding to the different forms of mutCALR in a complex with TPOR.

INCA035784 induced T-cell activation, proliferation, and cytotoxicity in type 1 and 2 mutCALR-expressing TF-1 cells. INCA035784 promoted HD T-cell-mediated killing in type-1-like mutCALR cells and HD cell-mediated functions towards type 1 and 2 mutCALR patient-derived CD34+ cells. 

INCA035784 did not bind to stress-induced surface-exposed CALR^WT. Additionally, it induced minimal levels of CRS-associated cytokines in HD PBMCs.

In autologous MF patient-derived xenograft models, INCA035784 led to reduction of myeloid cells (CD33+) and megakaryocytes (CD45+ CD41+) in BM, with no effect on CD71+ progenitor cells. INCA035784 shows potential as a therapeutic option for patients with MPN.