Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies

Puja Bhattacharyya; Richard I Christopherson; Kristen K Skarratt; Jake Z Chen; Thomas Balle; Stephen J Fuller

doi:10.3390/cancers15112881

Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies

Cancers (Basel). 2023 May 23;15(11):2881. doi: 10.3390/cancers15112881.

Authors

Puja Bhattacharyya^{1

2}, Richard I Christopherson³, Kristen K Skarratt^{1

4}, Jake Z Chen^{5

6}, Thomas Balle^{5

6}, Stephen J Fuller^{1

4}

Affiliations

¹ Sydney Medical School Nepean, Faculty of Medicine and Health, The University of Sydney, Kingswood, NSW 2750, Australia.
² Blacktown Hospital, Blacktown, NSW 2148, Australia.
³ School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
⁴ Nepean Hospital, Kingswood, NSW 2747, Australia.
⁵ Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
⁶ Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia.

Abstract

B cells are central to the adaptive immune response, providing long lasting immunity after infection. B cell activation is mediated by a cell surface B cell receptor (BCR) following recognition of an antigen. BCR signaling is modulated by several co-receptors including CD22 and a complex that contains CD19 and CD81. Aberrant signaling through the BCR and co-receptors promotes the pathogenesis of several B cell malignancies and autoimmune diseases. Treatment of these diseases has been revolutionized by the development of monoclonal antibodies that bind to B cell surface antigens, including the BCR and its co-receptors. However, malignant B cells can escape targeting by several mechanisms and until recently, rational design of antibodies has been limited by the lack of high-resolution structures of the BCR and its co-receptors. Herein we review recently determined cryo-electron microscopy (cryo-EM) and crystal structures of the BCR, CD22, CD19 and CD81 molecules. These structures provide further understanding of the mechanisms of current antibody therapies and provide scaffolds for development of engineered antibodies for treatment of B cell malignancies and autoimmune diseases.

Keywords: B cell; B cell receptor; CD19; CD22; CD81; cryo-electron microscopy; crystallography; monoclonal antibody.

Publication types

Review

Grants and funding

P.B. is supported by a scholarship from the Sydney West Translational Cancer Research Centre, the Cancer Institute of NSW. J.Z.C. is supported by the Australian Government Research Training Program.