Crystal structure of B-cell co-receptor CD19 in complex with antibody B43 reveals an unexpected fold

Proteins
Alexey TeplyakovGary L Gilliland

Abstract

CD19 is a transmembrane protein expressed on malignant B cells, but not in other lineages or other tissues, which makes it an attractive target for monoclonal antibody-mediated immunotherapy. Anti-CD19 antibody B43 was utilized in a bispecific T-cell engager (BiTE) blinatumomab that demonstrated potency for the treatment of relapsed acute lymphoblastic leukemia. To gain insight into the mechanism of action of the antibody, the crystal structure of B43 Fab was determined in complex with CD19 and in the unbound form. The structure revealed the binding epitope, explained the lack of cross-reactivity toward non-human species, and suggested the key-and-lock mechanism of antigen recognition. Most unexpectedly, the structure revealed a unique molecular topology of CD19. Rather than a tandem of c-type immunoglobulin folds predicted from the amino acid sequence, the extracellular domain of CD19 exhibits an elongated β-sandwich formed by two immunoglobulin folds by swapping their C-terminal halves. This is the first structure of CD19, which has no sequence homologs.

References

Aug 20, 1987·Journal of Molecular Biology·C Chothia, A M Lesk
Sep 15, 1982·Journal of Molecular Biology·A M Lesk, C Chothia
Oct 31, 2002·Immunologic Research·Robert H CarterStephen Brooks
May 5, 2006·The New England Journal of Medicine·Menno C van ZelmJosé L Franco
Jan 22, 2008·The Journal of Allergy and Clinical Immunology·Marc C Levesque, E William St Clair
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Aug 10, 2010·Acta Crystallographica. Section D, Biological Crystallography·Galina ObmolovaGary L Gilliland
Dec 6, 2012·Experimental Hematology & Oncology·Kemeng WangDelong Liu
Jul 11, 2013·Molecular Therapy. Nucleic Acids·Zakaria GradaNabil Ahmed
May 24, 2016·MAbs·Alexey TeplyakovGary L Gilliland
Dec 3, 2016·Nucleic Acids Research·UNKNOWN The UniProt Consortium
Feb 6, 2017·Immunology Letters·Xinchen LiYuekang Xu
Mar 2, 2017·The New England Journal of Medicine·Hagop KantarjianMax S Topp

❮ Previous
Next ❯

Citations

Mar 3, 2020·Frontiers in Bioengineering and Biotechnology·Elisabeth LobnerRenate Kunert
Apr 10, 2020·Monoclonal Antibodies in Immunodiagnosis and Immunotherapy·Shinji YamadaYukinari Kato
Aug 28, 2020·Frontiers in Immunology·Yifei Hu, Jun Huang
Jan 16, 2021·Science·Katherine J SusaStephen C Blacklow
Jul 18, 2021·The Journal of Biological Chemistry·June Ereño-OrbeaJean-Philippe Julien
Jun 27, 2019·Molecular Pharmaceutics·Justin R KlesmithPaul D Rennert
Nov 9, 2019·Biochemistry·Justin R KlesmithBenjamin J Hackel

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.