ALPHA-GALACTOSYL OLIGOSACCHARIDES CONJUGATED WITH POLYETHYLENE-GLYCOLAS POTENTIAL INHIBITORS OF HYPERACUTE REJECTION UPON XENOTRANSPLANTATION

Antibodies to an alpha-galactosyl saccharide structure are mainly resp onsible for hyperacute rejection after pig-to-primate xenotransplantat ion. The beneficial effect of alpha-galactosyl oligosaccharides has be en shown on the inhibition of anti-pig natural antibodies. We synthesi zed polyethylene glycol (PEG)conjugates of alpha-galactosyl disacchari de (Pi) and trisaccharide (Tri) as potential inhibitors of the rejecti on reaction. The half lives of Di, Tri, PEG-conjugated Pi (Pi-PEG) and PEG-conjugated Tri (Tri-PEG) were 18.1 +/- 2.3 min, 20.2 +/- 0.9 min, 38.7 +/- 2.8 min and 35.8 +/- 1.6 min, respectively. Furthermore, Pi- PEG and Tri-PEG showed biphasic clearance, and their half lives at the second phase were longer than 10 hours. PEG-conjugated oligosaccharid es (Pi-PEG, Tri-PEG) markedly inhibited cytotoxic action of human sera to pig kidney cell line (PK15) compared to unconjugated oligosacchari des (Pi, Tri). The binding of IgM antibodies to PK15 cells, however, w as more strongly blocked by unconjugated oligosaccharides than PEG-con jugated oligosaccharides. This phenomenon can be explained by the find ing that PEG has anti-complement activity and masks antigenic sites of oligosaccharides. In conclusion, conjugation of PEG to oligosaccharid es provided two beneficial effects; prolonged intravascular retention time and anti-complement activity, upon systemic application of the ol igosaccharides. The present findings opened a new approach to treatmen t of hyperacute rejection after xenotransplantation. (C) 1997 Academic Press.