October 25, 2024
Author(s): Courtney Flaherty
Fact checked by: Megan Hollasch
Unlike the array of JAK inhibitors available for the treatment of patients with myelofibrosis, the novel monoclonal antibody INCA033989 may have disease-modifying potential among those expressing CALR type 1 mutations, potentially addressing an area of need in myeloproliferative neoplasm (MPN) management, according to Daniel J. DeAngelo MD, PhD.
“With the 4 [FDA-approved] JAK inhibitors, we see clear improvements in symptoms, reduction in spleen [volume], and decreased counts for patients with polycythemia or essential thrombocytopenia, but we’re not seeing eradication and normalization of the bone marrow,” DeAngelo said in an interview with OncLive®. “We don’t know if this agent is going to change that, but the hypothesis is that [INCA033989] may be getting at the heart of the disease, although only for patients with CALR type 1 mutations.”
In engineered cell lines and primary CD34-positive cells from patients with MPN, INCA033989 was shown to antagonize mutant CALR–driven signaling and cellular proliferation. Moreover, in a mouse model of MPN with mutant CALR, administration of an INCA033989 mouse surrogate antibody prevented the development of thrombocytosis and accumulation of platelet-producing megakaryocytes in the bone marrow. The agent’s disease-modifying potential is supported by its reduction of pathogenic self-renewal among MPN cells expressing CALR mutations in both primary and secondary transplantations.1
These preclinical data support the agent’s ongoing investigation in a phase 1 study (NCT06034002) for patients with MPN.2