Journal Article

Antibody targeting of mutant calreticulin in myeloproliferative neoplasms

Mullally, Ann, Kramer, Frederike

2024

Overview

Mutations in calreticulin are one of the key disease‐initiating mutations in myeloproliferative neoplasms (MPN). In MPN, mutant calreticulin translates with a novel C‐terminus that leads to aberrant binding to the extracellular domain of the thrombopoietin receptor, MPL. This cell surface neoantigen has become an attractive target for immunological intervention. Here, we summarize recent advances in the development of mutant calreticulin targeting antibodies as a novel therapeutic approach in MPN. Overview of pathogenic mechanisms of mutant calreticulin (CALR) in myeloproliferative neoplasms (MPN) and potential ways to target the mutant calreticulin neoantigen by therapeutic monoclonal antibodies (mAb). 1: Mutant calreticulin is secreted and functions as an immunosuppressor. The mutant calreticulin novel C‐terminus is shown in red. 2: Aberrant binding of mutant calreticulin dimers to the thrombopoietin receptor MPL mediates receptor dimerization and leads to constitutive activation of JAK‐STAT signaling, promoting proliferation of MPN cells. Mutant calreticulin‐MPL binding occurs in the endoplasmic reticulum (ER), with the protein complex trafficking through the Golgi to the cell surface. 3: Therapeutic antibody targeting the novel C‐terminus of mutant calreticulin on the cell surface can prevent dimerization and activation of MPL (i.e. a blocking antibody). A mutant calreticulin antibody with an Fc component could be engineered to enable Fcγ receptor‐mediated immune cell targeting. 4: A bispecific approach targeting both MPL and mutant calreticulin could increase specificity and circumvent trapping of the mAb by secreted mutant calreticulin. 5: mAb‐toxin conjugates could increase efficacy. 6: The mutant calreticulin neoantigen could be targeted by engineered chimeric antigen receptor (CAR)‐T cells. 7: Bispecific antibodies could enable binding of cytotoxic CD3+ T‐cells to mutant calreticulin expressing MPN cells. 8: Circulating mutant calreticulin may bind the mAb and potentially act as a decoy, decreasing mAb availability. Figure was created using BioRender.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Amino acids / Animals / Bone marrow / C-Terminus / Calreticulin / Calreticulin - genetics / Calreticulin - metabolism / Cell surface / Humans / Kinases / Monoclonal antibodies / Mutants / Mutation / Myeloproliferative Disorders - drug therapy / Myeloproliferative Disorders - genetics / Myeloproliferative Disorders - immunology / Myeloproliferative Disorders - metabolism / Myeloproliferative Disorders - pathology / Neoantigens / Patients / Peptides / Receptors, Thrombopoietin - genetics / Receptors, Thrombopoietin - metabolism / Review / Reviews / Thrombopoietin / Transplants & implants / Tumors / Vaccines