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The Journal of Immunology, 2006, 177: 2994-3003.
Copyright © 2006 by The American Association of Immunologists, Inc.

High-Affinity Ligand Probes of CD22 Overcome the Threshold Set by cis Ligands to Allow for Binding, Endocytosis, and Killing of B Cells1

Brian E. Collins*, Ola Blixt*, Shoufa Han*, Bao Duong*, Hongyi Li*, Jay K. Nathan*, Nicolai Bovin{dagger} and James C. Paulson2,*

* Departments of Molecular Biology and Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92024; and {dagger} Shemyakin and Ovchinnokov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation

CD22 (Siglec-2) is a key regulator of B cell signaling whose function is modulated by interaction with extracellular glycan ligands mediated through its N-terminal Ig domain. Its preferred ligand is the sequence Sia{alpha}2-6Gal that is abundantly expressed on N-linked glycans of B cell glycoproteins, and by binding to CD22 in cis causes CD22 to appear "masked" from binding to synthetic sialoside probes. Yet, despite the presence of cis ligands, CD22 redistributes to sites of cell contact by binding to trans ligands on neighboring cells. In this study, we demonstrate the dynamic equilibrium that exists between CD22 and its cis and trans ligands, using a high-affinity multivalent sialoside probe that competes with cis ligands and binds to CD22 on native human and murine B cells. Consistent with the constitutive endocytosis reported for CD22, the probes are internalized once bound, demonstrating that CD22 is an endocytic receptor that can carry ligand-decorated "cargo" to intracellular compartments. Conjugation of the sialoside probes to the toxin saporin resulted in toxin uptake and toxin-mediated killing of B lymphoma cell lines, suggesting an alternative approach for targeting CD22 for treatment of B cell lymphomas.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Grants GM60938 and AI050143 (to J.C.P.) and GM25042 (to B.E.C.), GM62116 (to The Consortium for Functional Glycomics), and the Physico-Chemical Biology Program, RAS (to N.B.).

2 Address correspondence and reprint requests to Dr. James C. Paulson, 10550 North Torrey Pines Road, MEM L71, La Jolla, CA 92037. E-mail address: jpaulson{at}scripps.edu

3 Abbreviations used in this paper: eq., equivalent; CTP, cytidine 5'-triphosphate; BPC, N-biphenyl-4-carbonyl chloride; LacNAc, Galbeta1-4GlcNac; BPA, N-biphenyl-4-acetic acid; PAA, polyacrylamide; hCD22, human CD22; mCD22, murine CD22; LacNAc, Galbeta1-4GlcNAc; pNPP, p-nitrophenylphosphate.




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