New research showed that a nanotherapy delivering the drug midostaurin eliminated mast cells while sparing healthy cells in laboratory and mouse experiments. Developed by researchers at Northwestern University, this approach offers an early proof of concept for a more precise way to treat systemic mastocytosis (SM) and other diseases driven by overactive or overproduced mast cells.
The findings were published in the Journal of Allergy and Clinical Immunology.
The experimental treatment, called anti-Sig6-NPmidoFab, packages the approved drug midostaurin inside tiny nanoparticles. Midostaurin (sold as Rydapt) is a tyrosine kinase inhibitorTyrosine kinase inhibitor Targeted therapies designed to block the KIT D816V mutation that drives most cases of SM. Includes avapritinib, midostaurin and imatinib., a drug that blocks the growth signals fueling 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. overproduction. While effective, it also acts on many other targets, potentially causing side effects.
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To make delivery more precise, the researchers coated the nanoparticles with antibody fragments that bind to Siglec-6, a protein found on the surface of mast cells but few other cell types in the body. This allowed the particles to deliver the drug primarily to mast cells and largely bypass other cells.
In human mast cell lines, the targeted nanotherapy killed cells about as well as free midostaurin and worked even better in cells expressing higher levels of Siglec-6, including primary human skin mast cells.
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The clearest separation was observed in mice engineered to express human Siglec-6 on their mast cells: the targeted nanotherapy eliminated about 95% of mast cells, compared with roughly 47% to 57% for the free drug or untargeted nanoparticles. It also spared other immune cells, affecting about 5% of them, compared with 26% with the free drug.
“These findings provide proof-of-concept for the potential use of anti-Sig6-NPmidoFab in the treatment of mast cell malignancies, including mastocytosisMastocytosis Rare disease caused by the buildup of mast cells. Cutaneous mastocytosis primarily affects the skin and is more common in children, while systemic mastocytosis affects internal organs and is more common in adults. and mast cell leukemiaMast cell leukemia The most severe subtype of SM, caused by the rapid buildup of immature mast cells in the bone marrow and blood. Mast cell leukemia accounts for less than 5% of SM cases and has a poor prognosis.,” researchers noted.
Moreover, because the platform can be adapted by swapping the drug or the target, the researchers suggest it may one day apply to other mast cell and blood disorders. However, they cautioned that the construct still needs optimization before it is ready for use in humans.
