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J Am Chem Soc. 2017 Sep 13;139(36):12450-12458. doi: 10.1021/jacs.7b03208. Epub 2017 Aug 31.

CD22 Ligands on a Natural N-Glycan Scaffold Efficiently Deliver Toxins to B-Lymphoma Cells.

Author information

1
Departments of Molecular Medicine and Immunology & Microbiology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

Abstract

CD22 is a sialic acid-binding immunoglobulin-like lectin (Siglec) that is highly expressed on B-cells and B cell lymphomas, and is a validated target for antibody and nanoparticle based therapeutics. However, cell targeted therapeutics are limited by their complexity, heterogeneity, and difficulties in production. We describe here a chemically defined natural N-linked glycan scaffold that displays high affinity CD22 glycan ligands and outcompetes the natural ligand for the receptor, resulting in single molecule binding to CD22 and endocytosis into cells. Binding affinity is increased by up to 1500-fold compared to the monovalent ligand, while maintaining the selectivity for hCD22 over other Siglecs. Conjugates of these multivalent ligands with auristatin and saporin toxins are efficiently internalized via hCD22 resulting in killing of B-cell lymphoma cells. This single molecule ligand targeting strategy represents an alternative to antibody- and nanoparticle-mediated approaches for delivery of agents to cells expressing CD22 and other Siglecs.

PMID:
28829594
PMCID:
PMC5755971
DOI:
10.1021/jacs.7b03208
[Indexed for MEDLINE]
Free PMC Article

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