September 6, 2023
Vicki Moore, PhD
A review article published in the Journal of Cellular and Molecular Medicine details recent progress in the development of antibodies targeting mutated calreticulin, aimed at providing a novel therapy option for myeloproliferative neoplasms (MPN). The review was authored by Frederike Kramer, PhD, and Ann Mullally, MD, of Harvard Medical School in Boston, Massachusetts.
Calreticulin is encoded by the CALR gene and alterations in this gene are common drivers of the development of MPN. In most cases, these occur as 1 of 2 mutations in exon 9 of this gene, as Kramer and Mullally explained in their review. Approximately half of the patients with a CALR mutation have a 52-bp deletion, whereas approximately 30% of patients with a CALR mutation have an insertion of 5 bp in the sequence of this gene.
These types of mutations in CALR lead to a frameshift that causes formation of an altered C-terminus in calreticulin, resulting in the absence of an endoplasmic reticulum retention signal. The altered calreticulin is thus directed toward the cell’s surface, where it shows aberrant binding to the thrombopoietin receptor protein (MPL), with the interaction ultimately contributing to activation of the JAK-STAT signaling pathway and cell transformation.
Currently, patients with MPN are often treated with cytoreductive therapies. Allogeneic stem cell transplantation can be curative for patients with CALR-mutated MPN, but this approach carries risks of morbidity and mortality.
However, the interaction of altered calreticulin and MPL provides a possible substrate for a potential targeted treatment approach. Monoclonal antibodies (mAbs) directed at altered calreticulin have been the subject of research, and a range of studies have generated results indicating this may be a possible approach to treatment of CALR-mutated MPN.
Additional immunological approaches to treating MPN that have been under investigation involve peptide vaccination directed at altered calreticulin and T cell-directed targeting agents. Antibody-drug conjugates could also present a possible avenue of treatment, with these agents potentially binding to both mutated calreticulin and MPL within a complex, rather than binding to mutated calreticulin that has simply been secreted.
“Recent advances in identifying the mechanisms by which mutant calreticulin causes MPN paved the path for immunological targeting of CALR-mutant MPN cells, and specific mutant calreticulin targeting mAbs have been developed and found to be efficacious in preclinical mouse models,” the authors wrote in their report, also noting safety and efficacy with these agents have not yet been evaluated in this patient population.
Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.
Reference
Kramer F, Mullally A. Antibody targeting of mutant calreticulin in myeloproliferative neoplasms. J Cell Mol Med. Published online August 7, 2023. doi:10.1111/jcmm.17896