title: A soluble chimeric inhibitor of C3 and C5 convertases, complement activation blocker-2, prolongs graft survival in pig-to-rhesus monkey heart transplantation.
abstract: Complement plays a critical role in many pathologic processes and in xenograft rejection. Therefore, effective complement inhibitors are of great interest. In pig-to-primate organ transplantation, hyperacute rejection results from antibody deposition and complement activation. Complement activation blocker-2 (CAB-2), a recombinant soluble chimeric protein derived from human decay accelerating factor (DAF) and membrane cofactor protein, inhibits C3 and C5 convertases of both classical and alternative pathways. CAB-2 reduces complement-mediated tissue injury of a pig heart perfused ex vivo with human blood. Therefore, we studied the efficacy of CAB-2 when a pig heart is transplanted heterotopically into rhesus monkeys receiving no immunosuppression. Graft survival in three control monkeys was 1.26 +/- 0.2 h; it was markedly prolonged in eight monkeys that received CAB-2. Of the six monkeys that received a single dose of CAB-2 (15 mg/kg i.v.), four had graft survivals of 21, 95, 96, and 108 h, and two died at 7 to 11 h post-transplant with a beating graft, as a result of technical complications. The two monkeys given multiple doses of CAB-2 had graft survivals of 95 and 96 h. CAB-2 markedly inhibited complement activation, as shown by a strong reduction in generation of C3a and SC5b-9. At graft rejection, tissue deposition of iC3b, C4 and C9 was similar or slightly reduced from controls, and deposition of IgG, IgM, C1q and fibrin did not change. Thus, complement inhibition with CAB-2 abrogates hyperacute rejection of pig hearts transplanted into rhesus monkeys, but does not prevent delayed/acute vascular rejection. These studies demonstrate that the beneficial effects of complement inhibition on survival of a pig heart xenograft in rhesus monkeys are similar to those in other primate species and that CAB-2 may be useful in xenotransplantation and other complement-mediated conditions.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Salerno
authors.forename: David M
authors.initials: DM
authors.lastname: Kulick
authors.forename: C Grace
authors.initials: CG
authors.lastname: Yeh
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzman-Paz
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Higgins
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Benson
authors.forename: Soon J
authors.initials: SJ
authors.lastname: Park
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Shumway
authors.forename: R Morton
authors.initials: RM
authors.lastname: Bolman
authors.forename: Agustin P
authors.initials: AP
authors.lastname: Dalmasso
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage*; D003167:Complement Activation / Q000187:drug effects; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D006801:Humans; D008253:Macaca mulatta; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: D015703:Antigens, CD; D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; C410468:complement activation blocker 2, human; D050577:Complement C3-C5 Convertases