Dr DeAngelo on the Unique Mechanism of Action of INCA033989 in CALR-Mutated MPNs

"Currently, we [treat patients with MPNs by] blocking the JAK2 molecule, which blocks the signaling into the nucleus leading to less activation and proliferation. However, [available drugs are] not disease-modifying agents. The hope is that by blocking thatprocess, [INCA033989] may be a disease-modifying agent."

Daniel J. DeAngelo, MD, PhD, an institute physician at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, discusses the mechanism of action of INCA033989 in patients with CALR-mutated myeloproliferative neoplasms (MPNs).

INCA033989 is a monoclonal antibody specifically designed to target mutant CALR, a protein involved in the activation of the thrombopoietin receptor (TPO-R) signaling cascade, DeAngelo begins. Under normal physiological conditions, CALR undergoes intermittent dimerization in the presence of its ligand, allowing for controlled TPO-R activation, he explains. This process regulates downstream JAK2 signaling and cellular proliferation, he notes. 

In patients with CALR type 1 or type 2 mutations, however, the autodimerization of CALR occurs independently of ligand binding, DeAngelo states. This leads to constitutive activation of TPO-R and persistent JAK2 signaling, driving the aberrant cell proliferation characteristic of MPNs, he reports. CALR type 1 mutations are found in approximately 30% of patients with MPNs, making these mutations a significant therapeutic target, he emphasizes.

INCA033989 selectively binds to type 1–mutant CALR, inhibiting its ability to autodimerize, according to DeAngelo. This prevents aberrant TPO-R activation and subsequent JAK2-mediated oncogenic signaling, addressing a disease-initiating event rather than merely mitigating downstream effects of an overactivation signaling pathway, he says. Current therapies, such as JAK2 inhibitors, function by blocking nuclear signaling. Accordingly, these agents reduce proliferation but fail to produce disease-modifying effects, he explains.

Although clinical data with INCA033989 in human populations are not yet available, preclinical mouse models have demonstrated that this agent may restore normal megakaryopoiesis, thereby reducing abnormal platelet production, which is a hallmark of MPNs, DeAngelo continues. Unlike JAK inhibitors, which appear to have no correlation between marrow fibrosis and clinical responses in primary or secondary myelofibrosis, INCA033989 appears to normalize bone marrow architecture in preclinical models, he concludes.