An experimental antibody called barzolvolimab lowered the allergy-type activity of mast cells that carry the mutation behind most cases of systemic mastocytosis (SM), researchers reported in laboratory findings published in The Journal of Allergy and Clinical Immunology. Notably, the drug quieted these reactions without destroying the mutated cells themselves.
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In SM, mast cells build up in the body and release mediators that trigger a range of symptoms, including flushing, diarrhea and anaphylaxisAnaphylaxis A severe allergic reaction that can turn fatal without treatment. Patients with SM are at a higher risk of developing anaphylaxis.. Most adults with SM carry a gene change called KIT D816V. This mutation locks a protein on a mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body. called KIT permanently in the “on” position. Because KIT normally signals mast cells to grow, survive and stay ready to react, that constant signal causes cell accumulation and leaves them primed to overreact.
Read about how mutation burden might influence mastocytosis severity
A team of scientists in Berlin grew several types of human mast cells in the lab, including a newly engineered stem cell line carrying the KIT D816V mutation. They treated the cells with barzolvolimab, an antibody that blocks KIT.
Although barzolvolimab targets KIT, it couldn’t shut off this built-in signal, so the mutated cells survived while normal mast cells died. Even so, the antibody still turned down the mutated cells’ allergy-type reactions.
This effect showed up across every model the team tested. When the researchers triggered an allergic-style reaction through the immunoglobulin E (IgE) pathway, the route behind many real allergic responses, barzolvolimab blunted it in each cell type, including the mutated line, and more so as the dose rose. The team followed the effect through degranulation, the burst in which mast cells release their stored chemicals, and through a surface marker that appears when a cell is activated.
“KIT-dependent survival and activation are not equally affected by extracellular KIT blockade,” the researchers noted.
Because barzolvolimab calms the mutated cells rather than clearing them, the team described it as a way to silence mast cells rather than reduce their numbers. They suggested it could be a possible complement to symptom management alongside existing treatments for people with the KIT D816V mutation. However, larger studies in patients would be needed to define that role.
