2. Academic Validation
  3. Molecular basis of human CD22 function and therapeutic targeting

Molecular basis of human CD22 function and therapeutic targeting

  • Nat Commun. 2017 Oct 2;8(1):764. doi: 10.1038/s41467-017-00836-6.
June Ereño-Orbea 1,  Taylor Sicard 1 2,  Hong Cui 1,  Mohammad T Mazhab-Jafari 1,  Samir Benlekbir 1,  Alba Guarné 3,  John L Rubinstein 1 2 4,  Jean-Philippe Julien 5 6 7
Affiliations

Affiliations

  • 1 Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada, M5G 0A4.
  • 2 Department of Biochemistry, University of Toronto, Toronto, ON, Canada, M5S 1A8.
  • 3 Department of Biochemistry and Biomedical Science, McMaster University, Hamilton, ON, Canada, L8S 4L8.
  • 4 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada, M5G 1L7.
  • 5 Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada, M5G 0A4. jean-philippe.julien@sickkids.ca.
  • 6 Department of Biochemistry, University of Toronto, Toronto, ON, Canada, M5S 1A8. jean-philippe.julien@sickkids.ca.
  • 7 Department of Immunology, University of Toronto, Toronto, ON, Canada, M5S 1A8. jean-philippe.julien@sickkids.ca.
PMID: 28970495 DOI: 10.1038/s41467-017-00836-6
Abstract

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.

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