Of Mice and Men: Terminal Complement Inhibition With Anti-C5 Monoclonal Antibodies (2011)

The author provides perspective on clinical application of C5-specific antibody therapy for terminal complement inhibition in kidney transplantation. See article by Stegall et al on page 2405. The author provides perspective on clinical application of C5-specific antibody therapy for terminal complement inhibition in kidney transplantation. See article by Stegall et al on page 2405. Preformed antibodies confer immediate, short-term and long-term risks to allografts that are manifested by a broad spectrum of clinical presentations and physiologic and histopathologic changes. Antibody properties, including affinity, concentration, receptor-mediated signaling and Fc-related functions (complement activation, antibody-dependent cytotoxicity and FcR crosslinking) largely determine clinical phenotypes. Antibody effector functions have traditionally been classified as complement-dependent or complement-independent, thereby highlighting the importance of complement in antibody-mediated allograft injury. Complement-dependent mechanisms are thought to predominate in immediate/early posttransplant antibody-mediated rejection (AMR) that often presents in a virulent, or even fulminating fashion. Inhibition of complement activation resulting from high levels of preformed antidonor antibody during severe AMR episodes has been likened to a “calming of the storm” that provides a window for the patient (and the allograft) to recover from these potentially allograft- and life-threatening events. Several strategies for complement inhibition have been pursued by several pharmaceutical manufacturers as drug development targets for application in autoimmune diseases and organ transplantation. One approach, inhibition of C5 by monoclonal antibodies, was first reported in animal models as early as 1995 (1Kroshus TJ Rollins SA Dalmasso AP et al.Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-human xenotransplantation.Transplantation. 1995; 60: 1194-1202Crossref PubMed Google Scholar). This, and subsequent reports, demonstrated clinical potential in murine and large animal allograft and xenograft models in the late 1990s and early 2000s, and laid a substantial basic science foundation for clinical trials (2Wang H Arp J Liu W et al.Inhibition of terminal complement components in presensitized transplant models prevents antibody mediated rejection leading to long-term graft survival and accommodation.J Immunol. 2007; 179: 4451-4463Crossref PubMed Scopus (83) Google Scholar,3Rother RP Arp J Jiang J et al.C5 blockade with conventional immunosuppression induces long-term graft survival in presensitized recipients.Am J Transplant. 2008; 8: 1129-1142Crossref PubMed Scopus (56) Google Scholar). Eculizumab is a CDR-grafted humanized monoclonal antibody specific for the human complement C5 component with a hybrid human IgG2/IgG4 Fc heavy chain and human kappa light chain. Eculizumab has been approved by the FDA and European Medicines Agency for treatment of paroxysmal nocturnal hemoglobinuria. Eculizumab was first used in renal transplantation for treatment of refractory, severe AMR (4Locke JE Magro CM Singer AL et al.The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection.Am J Transplant. 2009; 9: 231-235Crossref PubMed Scopus (260) Google Scholar), and several recent reports have described treatment of atypical hemolytic uremic syndrome in kidney transplant recipients. In this issue, Stegall et al. report a nonrandomized, proof-of-concept study with eculizumab in renal transplant recipients at high risk for AMR (5Stegall MD Diwan T Raghavaiah S et al.Terminal complement inhibition decreases antibody mediated rejection in sensitized renal transplant recipients.Am J Transplant. 2011; 11: 2405-2413Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar). In this series, a remarkably low AMR incidence was observed with a favorable toxicity profile. Comparison of these results with a matched historical cohort supports the efficacy of eculizumab in the setting of renal transplantation in the presence of preformed antidonor antibody. Confirmation of these observations in the context of a randomized study is warranted. This study raises important questions, particularly the issue of efficacy in the setting of higher levels of antidonor HLA antibodies, as a substantial proportion of crossmatch-incompatible living donor kidney transplants have antidonor HLA antibody levels at higher levels than those allowed in this initial study. More detailed studies of eculizumab dosing and duration of therapy are needed, as well as experience in larger populations to assess infectious risk. Enhanced methods for prediction of the at-risk population should be developed, as over 50% of the control population did not experience AMR, and therefore may not benefit from eculizumab. Donor-specific antibody (DSA) levels decreased in a number of eculizumab-treated patients without additional antihumoral therapy. Interestingly, inflammatory infiltrates were minimal despite the presence of high DSA and significant C4d allograft deposits. These findings suggest that the clinical phenotype in eculizumab-treated patients resembles accommodation (2Wang H Arp J Liu W et al.Inhibition of terminal complement components in presensitized transplant models prevents antibody mediated rejection leading to long-term graft survival and accommodation.J Immunol. 2007; 179: 4451-4463Crossref PubMed Scopus (83) Google Scholar,5Stegall MD Diwan T Raghavaiah S et al.Terminal complement inhibition decreases antibody mediated rejection in sensitized renal transplant recipients.Am J Transplant. 2011; 11: 2405-2413Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar). It should be cautioned that, in contrast to ABO-incompatible transplants, apparent accommodation in the presence of HLA alloantibodies (DSA) often gives way to chronic rejection (6Haas M Rahman MH Racusen LC et al.C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: Correlation with histologic findings.Am J Transplant. 2006; 6: 1829-1840Crossref PubMed Scopus (194) Google Scholar). Complement-independent mediation of chronic rejection may result from HLA antigen ligation by DSA, resulting in endothelial cell activation, with expression of growth factor receptors and proliferation (7Zhang X Reed EF Effect of antibodies on endothelium.Am J Transplant. 2009; 9: 2459-2465Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Observation of transplant glomerulopathy in one of the 15 eculizumab treated patients led the authors to appropriately caution that longer follow up is needed to fully evaluate the incidence of transplant glomerulopathy. These observations suggest that HLA antibody elimination remains important for optimal long-term outcomes. These promising results hold promise for other patient populations, including ABO-incompatible kidney (and other solid organ) transplants, and also crossmatch-incompatible heart and lung transplant recipients, where high level antidonor HLA antibodies often preclude life-saving transplantation. An important hurdle to application and further development of this promising agent will be resistance of payers due to cost. Eculizumab drug cost (based on average wholesale price of $5627 for a 300-mg vial) of the regimen used in this study included $22 508 in the first 24 hours of transplantation, followed by a weekly cost of $11 254 per week for 4 weeks ($45 016 total), giving a total average wholesale price cost of $67 524 for the full course of therapy. If lower levels of eculizumab exposure prove effective, the cost barrier can be mitigated. The field of transplantation has entered a new age in which targeted therapies are being applied clinically for B-cell mediated responses in a manner similar to that employed over the last three decades for T-cell responses. These are certainly exciting times in transplantation. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.