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Glycobiology, 2000, Vol. 10, No. 2 141-148
© 2000 Oxford University Press

Xenotransplantation: in vitro analysis of synthetic {alpha}-galactosyl inhibitors of human anti-Gal{alpha}1->3Gal IgM and IgG antibodies

Robert Rieben1, Nicolai V. Bovin2, Elena Y. Korchagina2, Rafael Oriol3, Nikolay E. Nifant’ev4, Dimitrij E. Tsvetkov4, Mohamed R. Daha5, Paul J. Mohacsi and David H. Joziasse6

Department of Cardiology, University Hospital, CH-3010 Bern, Switzerland, 2Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117871, GSP–7, V-437 Moscow, Russia, 3INSERM U504 and University of Paris South XI, F–94807 Villejuif Cedex, France, 4Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 117913, B-334 Moscow, Russia, 5Department of Nephrology, Leiden University Medical Center, NL-2300 RC Leiden, The Netherlands, and 6Department of Medical Chemistry, Vrije Universiteit, NL-1081 BT Amsterdam, The Netherlands

Pig-to-human xenotransplantation might be an option to overcome the increasing shortage of human donor organs. However, naturally occurring antibodies in human blood against the Gal{alpha}1->3Gal antigen on pig endothelial cells lead to hyperacute or, if prevented, acute or delayed vascular rejection of the pig graft. The purpose of this study was therefore to evaluate synthetic oligosaccharides with terminal Gal{alpha}1->3Gal to inhibit antigen-binding and cytotoxicity of anti-{alpha}Gal antibodies against pig cells. Different oligosaccharides were synthesized chemically and by a combined chemico-enzymatic approach. These included monomeric di–, tri–, and pentasaccharides, a polyacrylamide-conjugate (PAA-Bdi), as well as di–, tetra–, and octamers of Gal{alpha}1->3Gal. All were tested for inhibitory activity by anti-{alpha}Gal ELISA and complement-dependent cytotoxicity tests. PAA-Bdi was the best inhibitor of binding as well as cytotoxicity of anti-{alpha}Gal antibodies. Monomeric oligosaccharides efficiently prevented binding of anti-{alpha}Gal IgG, but less well that of anti-{alpha}Gal IgM, with tri- and pentasaccharides showing a better efficacy than the disaccharide. The two trisaccharides Gal{alpha}1->3Galß1->4GlcNAc and Gal{alpha}1->3Galß1->3GlcNAc were equally effective. Oligomers of Gal{alpha}1->3Gal were more effective than monomers in blocking the binding of anti-{alpha}Gal IgG. However, they could not block IgM binding, nor could they match the efficacy of PAA-Bdi. We conclude that oligosaccharides with terminal Gal{alpha}1->3Gal, most effectively as PAA-conjugates, can prevent binding and cytotoxicity of human anti-{alpha}Gal in vitro. The PAA-Bdi conjugate might be most suited for use as a Sepharose-bound immunoabsorption material.

1 To whom correspondence should be addressed at: Department of Cardiology, University Hospital, CH-3010 Bern, Switzerland, or via email at rieben@dkf2.unibe.ch


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M. Duk, G. Kusnierz-Alejska, E. Y. Korchagina, N. V. Bovin, S. Bochenek, and E. Lisowska
Anti-{alpha}-galactosyl antibodies recognizing epitopes terminating with {alpha}1,4-linked galactose: human natural and mouse monoclonal anti-NOR and anti-P1 antibodies
Glycobiology, February 1, 2005; 15(2): 109 - 118.
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