Xenotransplantation: in vitro analysis of synthetic alpha-galactosyl inhibitors of human anti-Galalpha1->3Gal IgM and IgG antibodies

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Abstract
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 Galα1→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 Galα1→3Gal to inhibit antigen-binding and cytotoxicity of anti-αGal 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 Galα1→3Gal. All were tested for inhibitory activity by anti-αGal ELISA and complement-dependent cytotoxicity tests. PAA-Bdi was the best inhibitor of binding as well as cytotoxicity of anti-αGal antibodies. Monomeric oligosaccharides efficiently prevented binding of anti-αGal IgG, but less well that of anti-αGal IgM, with tri- and pentasaccharides showing a better efficacy than the disaccharide. The two trisaccharides Galα1→3Galβ1→4GlcNAc and Galα1→3Galβ1→3GlcNAc were equally effective. Oligomers of Galα1→3Gal were more effective than monomers in blocking the binding of anti-αGal IgG. However, they could not block IgM binding, nor could they match the efficacy of PAA-Bdi. We conclude that oligosaccharides with terminal Galα1→3Gal, most effectively as PAA-conjugates, can prevent binding and cytotoxicity of human anti-αGal in vitro. The PAA-Bdi conjugate might be most suited for use as a Sepharose-bound immunoabsorption material.

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