Molecular basis of human CD22 function and therapeutic targeting

• Published in: Nature communications 2017-10, Vol.8 (1), p.764-11, Article 764
• Main Authors: Ereño-Orbea, June, Sicard, Taylor, Cui, Hong, Mazhab-Jafari, Mohammad T., Benlekbir, Samir, Guarné, Alba, Rubinstein, John L., Julien, Jean-Philippe
• Format: Article
• Language: English
• Subjects: 631/250; 631/45/535/1258; 631/45/535/1261; 631/45/535/1266; Antibodies, Monoclonal, Humanized - ultrastructure; Autoimmune diseases; Autoimmunity - immunology; B-Lymphocytes - immunology; BASIC BIOLOGICAL SCIENCES; Binding; CD22 antigen; Cell activation; Conformation; Crystal structure; Crystallography, X-Ray; Electron microscopy; Glycosylation; Hematological diseases; Humanities and Social Sciences; Humans; Humoral immunity; Immunity; Immunity, Humoral - immunology; Immunology; Immunomodulation; Lectins; Lectins - immunology; Ligands; Lymphocytes B; Microscopy, Electron; Modulators; Molecular Targeted Therapy; multidisciplinary; Protein Conformation; SAXS; Science; Science (multidisciplinary); Sialic Acid Binding Ig-like Lectin 2 - immunology; Sialic Acid Binding Ig-like Lectin 2 - ultrastructure; Therapeutic targets; X-ray crystallography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00836-6

CD22 maintains a baseline level of B-cell inhibition to keep humoral immunity in check. As a B-cell-restricted antigen, CD22 is targeted in therapies against dysregulated B cells that cause autoimmune diseases and blood cancers. Here we report the crystal structure of human CD22 at 2.1 Å resolution, which reveals that specificity for α2-6 sialic acid ligands is dictated by a pre-formed β-hairpin as a unique mode of recognition across sialic acid-binding immunoglobulin-type lectins. The CD22 ectodomain adopts an extended conformation that facilitates concomitant CD22 nanocluster formation on B cells and binding to trans ligands to avert autoimmunity in mammals. We structurally delineate the CD22 site targeted by the therapeutic antibody epratuzumab at 3.1 Å resolution and determine a critical role for CD22 N-linked glycosylation in antibody engagement. Our studies provide molecular insights into mechanisms governing B-cell inhibition and valuable clues for the design of immune modulators in B-cell dysfunction. The B-cell-specific co-receptor CD22 is a therapeutic target for depleting dysregulated B cells. Here the authors structurally characterize the ectodomain of CD22 and present its crystal structure with the bound therapeutic antibody epratuzumab, which gives insights into the mechanism of inhibition of B-cell activation.