Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies.
| Title: | Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies. |
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| Authors: | Bhattacharyya, Puja, Christopherson, Richard I., Skarratt, Kristen K., Chen, Jake Z., Balle, Thomas, Fuller, Stephen J. |
| Source: | Cancers; Jun2023, Vol. 15 Issue 11, p2881, 20p |
| Subject Terms: | B cells, CELL receptors, MONOCLONAL antibodies, AUTOIMMUNE diseases, CELLULAR signal transduction, ELECTRON microscopy, MEMBRANE proteins, ANTIGENS |
| Abstract: | Simple Summary: The treatment of B cell malignancies was transformed by the development of a monoclonal antibody—rituximab—that targets CD20, a protein expressed on the surface of B cells. However, some types of B cell malignancies do not express CD20 or can reduce the expression of the protein to escape therapy. Consequently, there is a need to develop tailored therapies against other targets expressed by B cells. The structures of key B cell proteins, the B cell receptor, and its co-receptors CD22, CD19 and CD81, have recently been solved and provide the opportunity to guide development of new antibodies and other therapies targeted at malignant B cells. Here, we review high-resolution protein structures of the BCR, CD22, CD19 and CD81 molecules, treatments that have been developed against these targets and discuss structural features that will enable the design of novel antibodies. 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. [ABSTRACT FROM AUTHOR] |
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| Database: | Complementary Index |
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| Items | – Name: Title Label: Title Group: Ti Data: Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Bhattacharyya%2C+Puja%22">Bhattacharyya, Puja</searchLink><br /><searchLink fieldCode="AR" term="%22Christopherson%2C+Richard+I%2E%22">Christopherson, Richard I.</searchLink><br /><searchLink fieldCode="AR" term="%22Skarratt%2C+Kristen+K%2E%22">Skarratt, Kristen K.</searchLink><br /><searchLink fieldCode="AR" term="%22Chen%2C+Jake+Z%2E%22">Chen, Jake Z.</searchLink><br /><searchLink fieldCode="AR" term="%22Balle%2C+Thomas%22">Balle, Thomas</searchLink><br /><searchLink fieldCode="AR" term="%22Fuller%2C+Stephen+J%2E%22">Fuller, Stephen J.</searchLink> – Name: TitleSource Label: Source Group: Src Data: Cancers; Jun2023, Vol. 15 Issue 11, p2881, 20p – Name: Subject Label: Subject Terms Group: Su Data: <searchLink fieldCode="DE" term="%22B+cells%22">B cells</searchLink><br /><searchLink fieldCode="DE" term="%22CELL+receptors%22">CELL receptors</searchLink><br /><searchLink fieldCode="DE" term="%22MONOCLONAL+antibodies%22">MONOCLONAL antibodies</searchLink><br /><searchLink fieldCode="DE" term="%22AUTOIMMUNE+diseases%22">AUTOIMMUNE diseases</searchLink><br /><searchLink fieldCode="DE" term="%22CELLULAR+signal+transduction%22">CELLULAR signal transduction</searchLink><br /><searchLink fieldCode="DE" term="%22ELECTRON+microscopy%22">ELECTRON microscopy</searchLink><br /><searchLink fieldCode="DE" term="%22MEMBRANE+proteins%22">MEMBRANE proteins</searchLink><br /><searchLink fieldCode="DE" term="%22ANTIGENS%22">ANTIGENS</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Simple Summary: The treatment of B cell malignancies was transformed by the development of a monoclonal antibody—rituximab—that targets CD20, a protein expressed on the surface of B cells. However, some types of B cell malignancies do not express CD20 or can reduce the expression of the protein to escape therapy. Consequently, there is a need to develop tailored therapies against other targets expressed by B cells. The structures of key B cell proteins, the B cell receptor, and its co-receptors CD22, CD19 and CD81, have recently been solved and provide the opportunity to guide development of new antibodies and other therapies targeted at malignant B cells. Here, we review high-resolution protein structures of the BCR, CD22, CD19 and CD81 molecules, treatments that have been developed against these targets and discuss structural features that will enable the design of novel antibodies. 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. [ABSTRACT FROM AUTHOR] – Name: Abstract Label: Group: Ab Data: <i>Copyright of Cancers is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.3390/cancers15112881 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 20 StartPage: 2881 Subjects: – SubjectFull: B cells Type: general – SubjectFull: CELL receptors Type: general – SubjectFull: MONOCLONAL antibodies Type: general – SubjectFull: AUTOIMMUNE diseases Type: general – SubjectFull: CELLULAR signal transduction Type: general – SubjectFull: ELECTRON microscopy Type: general – SubjectFull: MEMBRANE proteins Type: general – SubjectFull: ANTIGENS Type: general Titles: – TitleFull: Combination of High-Resolution Structures for the B Cell Receptor and Co-Receptors Provides an Understanding of Their Interactions with Therapeutic Antibodies. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Bhattacharyya, Puja – PersonEntity: Name: NameFull: Christopherson, Richard I. – PersonEntity: Name: NameFull: Skarratt, Kristen K. – PersonEntity: Name: NameFull: Chen, Jake Z. – PersonEntity: Name: NameFull: Balle, Thomas – PersonEntity: Name: NameFull: Fuller, Stephen J. IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 06 Text: Jun2023 Type: published Y: 2023 Identifiers: – Type: issn-print Value: 20726694 Numbering: – Type: volume Value: 15 – Type: issue Value: 11 Titles: – TitleFull: Cancers Type: main |
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