Myelofibrosis is the most severe of the myeloproliferative neoplasms. It is a pre-leukaemic condition that causes scarring in the bone marrow, inflammatory symptoms (lethargy, itching, sweats), and abnormal blood cell counts (especially anaemia). Around half of patients with myelofibrosis die within 5 years and 20-30% develop acute myeloid leukaemia. Around one quarter of people with myelofibrosis have an acquired blood cell mutation in the gene, CALR, that encodes the calreticulin protein. CALR mutations cause abnormal activation of blood cell growth through a mechanism is poorly understood. CALR mutations are present in the myelofibrosis stem cells that are the origin of the disease. The main treatment for myelofibrosis is ruxolitinib, which does not target the CALR mutation specifically. Patients with CALR MF have some benefit from ruxolitinib, but it does not reverse the effects of the disease and most people will experience loss of response and progressive disease within 3-4 years.
We are developing a completely different approach to the treatment of myelofibrosis. We have designed an antibody that binds to the abnormal CALR protein on the surface of myelofibrosis cells. We have tested the antibody in myelofibrosis cells and shown that it blocks their growth, but has no effect on normal blood cells. In the next year we will perform more detailed studies to understand how the antibody binds to and blocks the effects of abnormal CALR. We will also use the antibody to treat mice with myelofibrosis to confirm its safety and effectiveness. This exciting research will improve our understanding of how abnormal CALR works, and may lead to a safer and more effective new treatment for myelofibrosis that targets the root cause of the disease.