A recombinant soluble chimeric complement inhibitor composed of human CD46and CD55 reduces acute cardiac tissue injury in models of pig-to-human heart transplantation

Background. Inasmuch as complement plays a critical role in many pathologic al processes and in xenograft rejection, efficient complement inhibitors ar e of great interest. Because the membrane-associated complement inhibitors are very effective, recombinant soluble molecules have been generated. Methods. We tested the efficacy of complement activation blocker-2 (CAB-2), a recombinant soluble chimeric protein derived from human decay accelerati ng factor (DAF, CD55) and membrane cofactor protein (MCP, CD46), in two mod els of pig-to-human xenotransplantation in which tissue injury is complemen t mediated. The in vitro model consisted of porcine aortic endothelial cell s and human serum, and the ex vivo model consisted of a porcine heart perfu sed with human blood. Results. In vitro, addition of CAB-8 to serum inhibited cytotoxicity and th e deposition of C4b and iC3b on the endothelial cells. Err vivo, addition o f CAB-S to human blood prolonged organ survival from 17.3+/-6.4 min in cont rols to 108+/-55.6 min with 910 nM (100 mu g/ml) CAB-2 and 219.8+/-62.7 min with 1820 nM (200 mu g/ml) CAB-2. CAB-2 also retarded the onset of increas ed coronary vascular resistance. The complement activity of the perfusate w as reduced by CAB-2, as was the generation of C3a and SC5b-9, The myocardia l tissues had similar deposition of IgG, IgM, and C1q; however, CAB-2 reduc ed the deposition of C3, C4, and C9, Hearts surviving >240 min demonstrated trace to no deposition of C9 and normal histologic architecture. Conclusion. These results indicate that CAB-2 can function as an inhibitor of complement activation and markedly reduce tissue injury in models of pig -to-human xenotransplantation and thus may represent a useful therapeutic a gent for xenotransplantation and other complement-mediated conditions.