Pre-clinical research results detailing the development and mechanism of action of INCA033989, a novel anti-mutant calreticulin (CALR)-targeted monoclonal antibody (mAbs) discovered by Incyte, shows that the investigational compound can alter disease course by reducing mutant CALR allele burden and thus may be an efficacious and safe treatment in patients with myelofibrosis (MF) and essential thrombocythemia (ET).

The data was featured in the Plenary Scientific Session at the 64th American Society of Hematology (ASH) Annual Meeting, held December 10-13, 2022 (Abstract #6. Session: Hematology Disease Topics & Pathways: Research, Diseases, Therapies, Myeloid Malignancies)  in New Orleans and virtually).[1]

Progressive disease
Myeloproliferative neoplasms (MPNs) are a closely related group of blood cancers in which the bone marrow, where the body’s blood cells are made, functions abnormally. MPNs are progressive blood cancers that can strike anyone at any age, but they are more common in older adults. Estimates of the prevalence of MPNs vary, but analysis of claims data suggests there may be as many as 200,000 people in the U.S. living with the most prevalent MPNs: myelofibrosis, polycythemia vera or essential thrombocythemia.

While the current treatment options for MPNs offer effective symptom management, they also result in high rates of discontinuation, which is caused by the emergence of resistance and inadequate drug tolerability. Hence, the development of new therapeutics selective for cells expressing calreticulin (CALR)-mutations (mutCALR) would allow targeting neoplastic cells without compromising normal hematopoiesis.

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“As a pioneer in the field of myeloproliferative neoplasms (MPNs), having brought the first FDA-approved treatment to patients, we are excited to have the opportunity to share details of our latest research,” noted Dash Dhanak, Ph.D., Executive Vice President and Chief Scientific Officer, Incyte.

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“We continue to apply our deep understanding of the complex biology of MPNs to expand treatment options for patients and the work on INCA033989 presented today reflects our progress toward this goal. We look forward to continuing to advance the development of this potential new treatment and to initiating clinical trials for INCA033989 next year,” Dhanak added.

Srdan Verstovsek, M.D., Ph.D.Professor of Medicine and hematologist-oncologist at MD Anderson. He is a global leader in myeloproliferative neoplasms (MPN) and the Founder/Director of the largest MPN Clinical Research Center worldwide. Photo courtesy: © 2022 The University of Texas MD Anderson Cancer Center. Used with permission.

Calreticulin (CALR-) mutations
Calreticulin (CALR) is an endoplasmic reticulum (ER)-resident protein involved in a spectrum of cellular processes. In healthy cells, CALR operates as a chaperone and Ca2+ buffer to assist correct protein folding within the ER. Besides favoring the maintenance of cellular proteostasis, these cell-intrinsic CALR functions support Ca2+-dependent processes, such as adhesion and integrin signaling, and ensure normal antigen presentation on MHC Class I molecules.[2]

CALR- mutations are responsible for disease development in approximately 25-35% of patients with MF and ET – two common types of MPNs. These mutations can include insertions or deletions in exon 9 of CALR, resulting (in both cases) in a frameshift that leads to the expression of a novel, positively charged C-terminus as well as the loss of the KDEL endoplasmic reticulum (ER)–retention signal.a The CALR- mutation (mutCALR) protein has a novel function that involves stable interaction with the thrombopoietin receptor (TPO-R). This interaction originates in the ER and is followed by the transit of the mutCALR/TPO-R complex to the cell surface, resulting in constitutive activation of JAK2/STAT signaling.

Inhibition of JAK/STAT signaling
INCA033989 binds with high affinity to mutant CALR and inhibits oncogenesis, the process of cells becoming cancerous, in cells expressing this oncoprotein.[3][4]

The investigational agent potently antagonizes CALR oncogenic function, resulting in selective inhibition of JAK/STAT signaling only in CALR-mutated cells with no effect on normal, non-oncogenic cells. This selectivity of action with INCA033989 results in the specific killing of tumor cells harboring the mutation and is suggestive of the potential to alter the course of disease in patients with CALR-mutant MF and ET.

“Diseases like myelofibrosis and essential thrombocythemia are often difficult to understand and treat, and unique approaches are necessary to develop effective and safe therapies,” said Srdan Verstovsek, M.D., Ph.D., Professor of Medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center.

“[..] this research provides strong rationale for the continued investigation and clinical advancement of INCA033989 – a novel treatment approach that targets CALR mutations,” Verstovsek concluded.

Note: a KDEL is a target peptide sequence in mammals and plants located on the C-terminal end of the amino acid structure of a protein. The KDEL sequence prevents a protein from being secreted from the endoplasmic reticulum (ER) and facilitates its return if it is accidentally exported.

Reference
[1] Reis E, Buonpane1 R, Celik H, Marty C, Lei1 A, Jobe F, Rupar M, et al. Discovery of INCA033989, a Monoclonal Antibody That Selectively Antagonizes Mutant Calreticulin Oncogenic Function in Myeloproliferative Neoplasms. Presented at the 64 ASH Annual Meeting, December 10-13, 2022.
[2] Fucikova J, Spisek R, Kroemer G, Galluzzi L. Calreticulin and cancer. Cell Res. 2021 Jan;31(1):5-16. doi: 10.1038/s41422-020-0383-9. Epub 2020 Jul 30. PMID: 32733014; PMCID: PMC7853084.
[3] Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013 Dec 19;369(25):2391-2405. doi: 10.1056/NEJMoa1312542. Epub 2013 Dec 10. PMID: 24325359; PMCID: PMC3966280.
[4] Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, et al. Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013 Dec 19;369(25):2379-90. doi: 10.1056/NEJMoa1311347. Epub 2013 Dec 10. PMID: 24325356.

Featured image: The ASH Store at the American Society of Hematology 61th Annual Meeting at the Orange County Convention Center. Photo courtesy © 2019. ASH/Scott Morgan. Used with permission

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