INCA033989 May Address Need for Disease-Modifying Therapies in Myelofibrosis

Daniel J. DeAngelo MD, PhD

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

In the interview, DeAngelo, who served as chair of a recent State of the Science Summit™ on hematologic malignancies, discussed INCA033989’s unique mechanism of action and how this differs from that of JAK inhibitors. He also highlighted ways the agent could address unmet needs in MPN by re-establishing normal megakaryopoiesis and reducing fibrosis. DeAngelo is a professor of medicine at Harvard Medical School, as well as a physician and chief of the Division of Leukemia at Dana-Farber Cancer Institute in Boston, Massachusetts.

OncLive: How does the monoclonal antibody INCA033989 target CALR mutations in MPN?

DeAngelo: This [agent] is specifically targeting calreticulin. Normal calreticulin will intermittently dimerize depending on whether there’s a ligand [present and will then bind to] the surface of the thrombopoietin receptor [TPO-R]. This is very important in terms of initiating the cascade for [TPO-R] activation and signaling.

In patients with [either] CALR type 1 or 2 mutations, there’s autodimerization. That is, the calreticulin is consistently dimerized, which leads to activation of [TPO-R] regardless of the ligand and [subsequent] activation of JAK2, leading to [oncogenic cell] proliferation. This monoclonal antibody binds to type 1 mutated calreticulin and abrogates the ability of calreticulin to dimerize. Therefore, we don’t get the initiation of signaling through the TPO-R, and activation of the JAK2 signaling cascade [is prevented].

In what ways does this agent differ from other currently available therapies for MPN?

This is a focus on a disease-initiating event. There are 4 different mutations that are [commonly] seen in patients with MPN. Focusing on myelofibrosis, we have JAK2 and MPL mutations, the more common CALR type 1 mutations, and the less common CALR type 2 mutations. CALR type 1 [mutations are present in] approximately [30%] of patients [with MPN].

Currently, we [treat these patients 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 the process, [INCA033989] may be a disease-modifying agent. Now we don’t [have data on its activity] in human beings; however, in mouse models, INCA033989 seems to block some of the abnormal platelet manufacturing, which is one hallmark of the disease. The re-establishment of normal megakaryopoiesis, or platelet growth, and the bone marrows in mice [appears] normal. That’s what we don’t see with JAK inhibitors. In fact, there’s no correlation between marrow fibrosis and responses [with JAK inhibitors] in patients with either primary or secondary myelofibrosis.

What gaps in myelofibrosis management could a potentially disease-modifying agent such as INCA033989 address?

What we can do right now is improve symptoms and reduce the size of the spleen. Peculiarly, there is an association with an improvement in survival, [and] the ability to get patients to stem cell transplant if they’re of appropriate age and health. All these things are [achievable] with the current JAK2 inhibitors, but what they don’t do is change the underlying disease base. That’s an unmet need. Whether this agent will fulfill the criteria of a disease-modifying agent is unclear. [However], it’s possible that in a patient with CALR type 1–mutated myelofibrosis, the fibrosis may go away as we re-establish normal megakaryopoiesis [and] the cytokine cascade that leads to the development of fibrosis [could] be blocked. We don’t know if that’s going to be the case, but that is the hope.

References

1. Reis E, Buonpane R, Celik H, et al. Selective targeting of mutated calreticulin by the monoclonal antibody INCA033989 inhibits oncogenic function of MPN. Blood. Published online September 10, 2024. doi:10.1182/blood.2024024373
2. A study to evaluate INCA033989 administered in participants with myeloproliferative neoplasms. ClinicalTrials.gov. Updated May 30, 2024. Accessed October 23, 2024. https://clinicaltrials.gov/study/NCT06034002