Structural details of monoclonal antibody m971 recognition of the membrane-proximal domain of CD22

Author:

Ereño-Orbea, June

Liu, Xianglei

Sicard, Taylor

Kucharska, Iga

Li, Wei

Borovsky, Dorota

Cui, Hong

Feng,Yang

Dimitrov, Dimiter S

Julien, Jean-Philippe
Author Address

Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 0A4; Ikerbasque Basque Foundation for Science, Bilbao (Bizkaia), Spain 48013., Department of Medicine, Division of Infectious Diseases, University of Pittsburgh, PA, USA 15261., Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 0A4; Department of Biochemistry, University of Toronto, Toronto, ON, Canada M5S 1A8., Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 0A4., Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8., Protein Interactions Group, Center for Cancer Research Nanobiology Program, Center for Cancer Research, National Institutes of Health, Frederick, Maryland, USA 21702., Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 0A4; Department of Biochemistry, University of Toronto, Toronto, ON, Canada M5S 1A8; Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8. Electronic address: jean-philippe.julien@sickkids.ca.,

Abstract:

Cluster of differentiation-22 (CD22) belongs to the sialic acid-binding immunoglobulin (Ig)-like lectin family of re-ceptors that is expressed on the surface of B cells. It has been classified as an inhibitory coreceptor for the B-cell receptor because of its function in establishing a baseline level of B-cell inhibition. The restricted expression of CD22 on B cells and its inhibitory function make it an attractive target for B-cell depletion in cases of B-cell malignancies. Genetically modified T cells with chimeric antigen receptors (CARs) derived from the m971 antibody have shown promise when used as an immunotherapeutic agent against B-cell acute lymphoblastic leukemia. A key aspect of the efficacy of this CAR-T was its ability to target a membrane-proximal epitope on the CD22 extracellular domain; however, the molecular details of m971 recognition of CD22 have thus far remained elusive. Here, we report the crystal structure of the m971 fragment antigen-binding in complex with the two most membrane-proximal Ig-like domains of CD22 (CD22(d6-d7)). The m971 epitope on CD22 resides at the most proximal Ig domain (d7) to the membrane, and the antibody paratope contains electrostatic surfaces compatible with interactions with phospholipid head groups. Together, our data identify molecular details underly-ing the successful transformation of an antibody epitope on CD22 into an effective CAR immunotherapeutic target.

See More

Author Address