Selective elimination of mast cells via Siglec-6-targeted nanodelivery of drug payload.

Abstract

Mast cell elimination through sialic acid immunoglobulin-like lectin 6 (Siglec-6) is a promising, yet minimally explored strategy for diseases characterized by mast cell overactivity or overproduction. We combined nanotechnology with cell-free protein synthesis to develop a therapeutic strategy (anti-Sig6-NPmidoFab) for selectively eliminating mast cells. Nanocarriers are loaded with the protein kinase inhibitor midostaurin and conjugated with cell-free protein synthesis-enabled clickable, synthetically dimerized anti-Siglec-6 antibody fragments to selectively target Siglec-6-expressing mast cells. Using human mast cell lines and primary human mast cells as well as a Siglec-6 knock-in mouse model and a humanized mast cell malignancy mouse model, we demonstrated selective elimination of Siglec-6-positive mast cells with reduced off-target effects on Siglec-6-negative cells. This approach offers new treatment strategies for malignant and nonmalignant mast cell-mediated disease with potential for broad application.