A monoclonal antibody may be effective for treating CALR-mutant myeloproliferative neoplasms (MPNs), according to preclinical research presented at the 2022 ASH Annual Meeting.
The antibody, INCA033989, demonstrated activity in cells from MPN patients and a mouse model of essential thrombocythemia.
INCA033989 is fully human IgG1 antibody that selectively binds to mutant CALR, explained study presenter Edimara Reis, PhD, of Incyte Corporation in Wilmington, Delaware.
In experiments with Ba/F3 cells, Dr Reis and colleagues found that INCA033989 binds to mutant CALR and inhibits oncogenic signaling. The researchers also found that INCA033989 inhibited cell proliferation and induced death in mutant CALR cells. INCA033989 appeared to have no functional effect on Ba/F3 cells not expressing mutant CALR.
The researchers also tested INCA033989 in CD34+ cells isolated from patients with MPNs. The team found that INCA033989 inhibits STAT5 phosphorylation in CD34+ CALR mutant cells. INCA033989 also inhibited proliferation and differentiation of mutant CALR hematopoietic stem and progenitor cells.
In a mouse model of essential thrombocythemia, INCA033989 selectively decreased levels of mutant CALR-positive platelets, re-established normal megakaryopoiesis, and selectively targeted mutant CALR disease-initiating clones.
“These data collectively provide strong rationale for the clinical investigation of INCA033989 in myelofibrosis and essential thrombocytopenia patients with CALR mutations, and a phase 1 study is planned to initiate in 2023,” Dr Reis concluded.
Disclosures: This research was supported by Incyte Corporation. Some study authors declared relationships, including employment, with the company. Please see the original reference for a full list of disclosures.
Reis E, Buonpane R, Celik H, et al. Discovery of INCA033989, a monoclonal antibody that selectively antagonizes mutant calreticulin oncogenic function in myeloproliferative neoplasms (MPNs). Presented at ASH 2022. December 10-13, 2022. Abstract 6.