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

• Published in: Journal of the American Chemical Society Vol. 139; no. 36; pp. 12450 - 12458
• Main Authors: Peng, Wenjie, Paulson, James C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.09.2017; Amer Chemical Soc
• Subjects: Animals; antibodies; Antineoplastic Agents - administration & dosage; B-cell lymphoma; B-lymphocytes; binding capacity; Cell Line, Tumor; Chemistry; Chemistry, Multidisciplinary; CHO Cells; Cricetulus; Endocytosis; Humans; lectins; Ligands; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Mice; nanoparticles; neoplasm cells; Physical Sciences; Polysaccharides - metabolism; Science & Technology; Sialic Acid Binding Ig-like Lectin 2 - metabolism; therapeutics; toxins; LECTIN; RECOGNITION; TOLERANCE; O-LINKED GLYCANS; ACETYLLACTOSAMINE; SIALYLOLIGOSACCHARIDE; SIGLEC-G; ENDOCYTOSIS; SIALIC ACIDS; BINDING
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.7b03208

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.