Targeting Mutant Calreticulin in MPNs with INCA033989: A Novel Monoclonal Antibody Approach

Calreticulin mutations contribute to the development of myeloproliferative neoplasms (MPNs) in a significant portion of patients. These mutations alter the CALR protein, leading to a change in function and interaction with the thrombopoietin receptor, which in turn activates the JAK2/STAT pathway. Current treatments for MPNs manage symptoms but often lead to discontinuation due to resistance and side effects.

A new monoclonal antibody, INCA033989, has been identified that specifically targets the mutated form of CALR (mutCALR) and its role in disease progression. This antibody was developed through a series of selections and modifications, resulting in a high-affinity, human IgG1 that binds to mutCALR and inhibits the TPO-R signaling pathway. INCA033989 has been shown to disrupt the signaling by preventing the dimerization of TPO-R and reducing cell proliferation, without affecting cells that do not express mutCALR.

Combining INCA033989 with ruxolitinib, a JAK1/2 inhibitor, has demonstrated a synergistic effect in inhibiting cell growth, suggesting that the antibody can enhance the effectiveness of existing treatments even at lower doses.

The antibody's impact on CD34+ cells from MPN patients was also tested, revealing that INCA033989 binds to these cells expressing mutCALR and suppresses the JAK2/STAT pathway activation in a dose-dependent manner. This effect was specific to mutCALR cells, with no effect observed in cells from healthy individuals or those with a different mutation.

In an in vivo model using mice, treatment with INCA033989 over 10 weeks successfully prevented the development of thrombocytosis by reducing the number of mutCALR-positive platelets. The treatment also led to a significant decrease in the percentage of precursor and progenitor cells of mutCALR origin, including megakaryocytes and long-term hematopoietic stem cells, without affecting overall bone marrow cellularity.

The study concludes that INCA033989 is a potent monoclonal antibody that selectively targets mutCALR, normalizing TPO-R signaling in patient-derived cells and in an MPN model. The antibody is currently under investigation for its therapeutic potential in MPN patients.