Researchers Identify INCA033989 as a Potential Treatment for Myeloproliferative Neoplasms

Data from a study published in Blood demonstrates the therapeutic potential of INCA033989 as the first targeted therapy for myeloproliferative neoplasms (MPNs) that does not interfere with normal blood cell production. Existing therapeutic options for MPNs are effective at symptom management but have high discontinuation rates due to resistance and inadequate drug tolerability. The development of INCA033989 opens pathways to more effective, targeted options with disease-modifying potential without any negative impact on surrounding blood cells.¹

The development of INCA033989 has positive implications for the evolving treatment landscape of patients with MPNs. Image Credit: © Anna - stock.adobe.com

MPNs are a group of malignancies characterized by the overproduction of red and white blood cells and is an umbrella for 6 different disease types: myelofibrosis (MF), essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Calreticulin (CALR) mutations are responsible for disease development in 20% to 30% of patients with MPNs, which can be either insertions or deletions in exon 9 of CALR. The mutated CALRprotein (mutCALR) is responsible for the stable interaction with thrombopoietin receptors (TPO-R), which are crucial for controlling blood cell production.^2,3

Janus kinase (JAK) inhibitors, such as ruxolitinib (Jakafi; Incyte Corp), are the recommended treatment options for patients with MF or other MPNs; however, they are associated with adverse effects (AEs), namely grade 3 or 4 anemia. INCA033989 is a high affinity, fully human immunoglobulin G1 selective monoclonal antibody targeting mutCALR-driven oncogenesis to suppress TPO-R signaling, thereby preventing the proliferation and progression of disease. According to data from the original study announcing the development of this agent, there was an observed synergism between INCA033989 and ruxolitinib which resulted in the inhibition of cell proliferation and indicated the ability of INCA033989 to enhance the efficacy of ruxolitinib.^3,4

In the study, the authors found that INCA033989 also binds to CD34+ cells collected from patients with MPN. By binding to CD34+, the mutCALR-driven activation of the JAK2/STAT pathway is inhibited and the decreased proliferation of mutCALR hematopoietic stem and progenitor cells and megakaryocytes in a dose-dependent manner.⁴

The capabilities of INCA033989 were also demonstrated in a competitive engraftment mouse model consisting of 30% SCL-Cre-ERT/mutCALRand 70% WT CALR UBC-GFP competitor bone marrow cells into lethally irradiated recipient mice. The authors found that a 10-week treatment with the monoclonal antibody prevented the development of thrombocytosis by selectively decreasing mutCALR-positive platelets, as well as suppressed the mutCALR-induced accumulation of megakaryocytes in the bone marrow.⁴

The development of INCA033989 has positive implications for the evolving treatment landscape of patients with MPNs without the negative AEs associated with existing therapies. Study of the agent is being advanced to investigation in patients, potentially leading to its further development as a monotherapy and combination treatment and offering patients with this rare, fatal disease renewed hope and safe, efficacious therapeutic options.

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. September 10, 2024. doi:10.1182/blood.2024024373

2. Chronic myeloproliferative neoplasms treatment (pdq®)–patient version. National Cancer Institute. November 17, 2023. Accessed September 26, 2024. https://www.cancer.gov/types/myeloproliferative/patient/chronic-treatment-pdq#:~:text=chronic%20myeloproliferative%20neoplasms.-,Myeloproliferative%20neoplasms%20are%20a%20group%20of%20diseases%20in%20which%20the,mature%20blood%20cells%20over%20time

3. 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). Blood. November 15, 2022. doi: 10.1182/blood-2022-159435

4. Study demonstrates safety, efficacy of luspatercept for mf-related anemia. Pharmacy Times. September 19, 2024. Accessed September 26, 2024. https://www.pharmacytimes.com/view/study-demonstrates-safety-efficacy-of-luspatercept-for-mf-related-anemia