Structural glycobiology of antibody recognition in xenotransplantation and cancer immunotherapy

Abstract

Carbohydrate antigens recognized by “natural” or preformed and elicited antibodies are central to transplantation/transfusion rejection across ABO blood group and species (xenotransplantation) barriers and are also promising candidates for cancer immunotherapy (Ramsland 2005). The key carbohydrate determinants (epitopes) recognized by antibodies are synthesized by a series of intracellular glycosyltransferases and are expressed on the surface of cells as glycolipids and glycoproteins. Often the minimal carbohydrate epitopes are located at the terminal end of more complex oligosaccharide chains, which result in these epitopes being displayed at a wide range of surface densities and contexts (e.g., glycolipids or glycoproteins). For example, many tumor-associated carbohydrate antigens are broadly expressed at very high densities on the cell surface of primary and metastatic tumors, but the same carbohydrates occur at much lower levels and are typically restricted to a few cell types in healthy tissues (Scott and Renner 2001; Ezzelarab et al. 2005; Kobata and Amano 2005; Cazet et al. 2010). Thus, antibodies with similar specificities for individual carbohydrate epitopes can display different and often selective cell-binding profiles, based on the unique presentation of the carbohydrates on the target cells.In this chapter, we discuss the structural glycobiology of the key antibody–carbohydrate interactions important in xenotransplantation and cancer immunotherapy. Progress in both fields is reliant on further mechanistic knowledge of the underlying complex biosynthetic pathways and the structural basis for antibody recognition of isolated and cellular forms of the target carbohydrates. Recent progress in bioinformatics, synthesis of complex carbohydrates and analysis of their interactions with proteins [reviewed in (Seeberger 2008; Taylor and Drickamer 2009; Frank and Schloissnig 2010)] is facilitating the experimental determination and interpretation of three-dimensional (3D) structures of antibody–carbohydrate complexes. Furthermore, advances in computational (in silico) methods [reviewed in (DeMarco and Woods 2008; Woods and Tessier 2010; Yuriev et al. 2011)] are revealing much needed complementary 3D information about antibody recognition of carbohydrates.