L-select
in mediates extravasation of leukocytes from blood
into the surround
ing tissue dur
ing
inflammation and is therefore a therapeutical target
in certa
in overwhelm
ing
immune reactions. In this study, we characterized an L-select
in specific block
ing DNA aptamer with respect to nucleotide composition and target b
ind
ing. Introduction of deletions and nucleotide exchanges resulted
in an optimized DNA sequence but preservation of the IC
50 in the low nanomolar range. The
inhibitory potential was significantly
increased when the aptamer was displayed as a di- and trimer connected via appropriate l
inker length. Similar to monoclonal antibodies, trimer yielded picomolar IC
50 values
in a competitive b
ind
ing
assay. In comparison to the monovalent aptamer, the trivalent assembly reduced
PBMC interactions to L-select
in ligands 90-fold under shear and exerted superior
inhibition of PBMC roll
ing
in vivo. In conclusion, our work demonstrates the feasibility of optimiz
ing aptamer sequences and shows that multivalent ligand presentation enables superior adhesion receptor target
ing.
From the Clinical Editor
During inflammation, leukocytes extravasate from blood vessels under chemotaxic signals. The presence of L-selectin on endothelium acts as a mediator for the extravasation process. In this study, the authors investigated an L-selectin specific blocking DNA aptamer in various forms, as inhibitors to leukocyte binding and extravasation. This new approach confirmed the potential use of aptamers in clinical setting.