INCA033989: novel investigational agent for CALR-mutated MPN

The novel monoclonal antibody INCA033989 is a potent antagonist of mutant calreticulin (CALR) function, selectively inhibiting the proliferation of CALR-mutated haematopoietic stem and progenitor cells (HSPCs), and potentially changing the course of disease in essential thrombocythemia and myelofibrosis by targeting disease-initiating cells. A phase 1 study of INCA033989 is planned to be launched in 2023.

“Myeloproliferative neoplasms (MPN) are a group of chronic myeloid blood cancers that develop following the acquisition of mutations in haematopoietic stem cells that subsequently drive overproduction of cells of the myeloid lineage,” outlined Prof. Bethan Psaila (University of Oxford, UK). “The same genetic lesions result in diverse clinical manifestations. Current therapies do not selectively target the MPN clone.” She continued to explain that CALR mutations are present in a substantial proportion of patients with MPN that do not harbour the JAK2V617 mutation [1].

INCA033989 is a fully human, mutant CALR-specific monoclonal antibody, antagonising mutant CALR-induced signalling, and oncogenic function. Dr Edimara Reis (Incyte Corporation, DE, USA) discussed the most important findings of the study that evaluated this novel monoclonal antibody [2], summarised as follows:

INCA033989:

• selectively binds to mutant CALR on engineered Ba/F3 cells, reverts mutant CALR-induced TPOR dimerisation on CALR-mutated or HAP1 wildtype cells and inhibits mutant CALR-induced oncogenic signalling.
• selectively inhibits cell proliferation and induces death of CALR-mutated cells and selectively inhibits pSTAT5 in primary CD34-positive CALR-mutated cells of patients with MPN and inhibits the proliferation of CALR-mutated HSPCs from healthy donors or patients with MPN
• In a murine model of essential thrombocythemia, an INCA033989 surrogate restored haematologic and molecular responses and re-established normal megakaryopoiesis in a murine model and selectively targeted CALR-mutated disease-initiating clones

According to the authors, these results warrant further investigation of INCA033989 in MPN, especially in patients with myelofibrosis or essential thrombocythemia with CALR mutations.

1. Klampfl T, et al. N Engl J Med. 2013;369:2379–2390.
2. Reis E, et al. Discovery of INCA033989, a Monoclonal Antibody That Selectively Antagonizes Mutant Calreticulin Oncogenic Function in Myeloproliferative Neoplasms (MPNs). Abstract 6, ASH 64^th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.

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Posted on 20 February 2023