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Human Anti-CXCR4 Antibodies Undergo V_H Replacement, Exhibit Functional V-Region Sulfation, and Define CXCR4 Antigenic Heterogeneity¹

Chen Xu^*,, Jianhua Sui^*,, Hong Tao^*, Quan Zhu^*, and Wayne A. Marasco^2,*,

^* Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115

The chemokine receptor CXCR4 and its ligand stromal-derived factor-1 (SDF-1/CXCL12) are essential for many biological processes and various pathological conditions. However, the relationship between CXCR4 antigenic structure and SDF-1-mediated biological responses is poorly understood. In this report, a panel of human anti-CXCR4 Abs were isolated and used to explore CXCR4 antigenic heterogeneity and function. Multiple fixed CXCR4 antigenic isoforms were detected on the surface of hemopoietic cells. Epitope mapping studies demonstrated the complex nature of the surface-exposed CXCR4 epitopes. Ab-mediated inhibition of chemotaxis correlated strongly with binding affinity, epitope recognition, as well as the level of CXCR4 isoform expression. In addition, detailed genetic analyses of these Abs showed evidence of V_H replacement. Importantly, structural and biochemical studies demonstrated tyrosine sulfation in novel regions of the V genes that contributed bidirectionally to the binding activity of the Abs. These data provide the first evidence that functional tyrosine sulfation occurs in self-reactive Abs and suggest a potential new mechanism that may contribute to the pathogenesis of Ab-mediated autoimmune disease. These Abs also provide valuable tools to explore the selective in vivo targeting of CXCR4 isoforms that may be preferentially expressed in certain disease states and involved in steady-state CXCR4-SDF-1 homeostasis.

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 AI060456 and AI52829 (to W.A.M.), AI58804 (to Q.Z.), as well as a Susan Komen Postdoctoral Fellowship PDF0202044 (to J.S.) from the Susan Komen Breast Cancer Foundation.

² Address correspondence and reprint requests to Dr. Wayne A. Marasco, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115. E-mail address: wayne_marasco{at}dfci.harvard.edu

³ Abbreviations used in this paper: SDF, stromal-derived factor; ECL, extracellular loop; PMPL, paramagnetic proteoliposome; GMFI, geometric mean fluorescence intensity; FW, framework domain; TM, transmembrane domain; MD, multidomain; Nt, N-terminal; VH/VL, variable region of Ig H chain or L chain.