title: Complement Inhibition for Prevention and Treatment of Antibody-Mediated Rejection in Renal Allograft Recipients.
abstract: Therapeutic interventions aimed at the human complement system are recognized as potentially important strategies for the treatment of inflammatory and autoimmune diseases because there is often evidence of complement-mediated injury according to pathologic assessments. In addition, there are a large number of potential targets, both soluble and cell bound, that might offer potential for new drug development, but progress in this area has met with significant challenges. Currently, 2 drugs are approved aimed at inhibition of complement activation. The first option is eculizumab (anti-C5), which is approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Eculizumab has also been studied in human transplantation for the treatment and prevention of antibody-mediated rejection (ABMR). Initial data from uncontrolled studies suggested a significant benefit of eculizumab for the prevention of ABMR in highly HLA-sensitized patients, but a subsequent randomized, placebo-controlled trial failed to meet its primary endpoint. Anecdotal data, primarily from case studies, showed benefits in treating complement-mediated ABMR. A second approved complement-inhibiting therapy is C1 esterase inhibitor (C1-INH), which is approved for use in patients with hereditary angioedema, a condition caused by mutations in the gene that codes for C1-INH. A recent placebo-controlled trial of C1-INH for prevention of ABMR in HLA-sensitized patients found that the drug was safe, with evidence for inhibition of systemic complement activation and complement-activating donor-specific antibodies. Other drugs are now under development.
authors.affiliation: Transplant Immunotherapy Program, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: stan.jordan@cshs.org.
authors.forename: S C
authors.initials: SC
authors.lastname: Jordan
authors.affiliation: Transplant Immunotherapy Program, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: J
authors.initials: J
authors.lastname: Choi
authors.affiliation: Transplant Immunotherapy Program, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: J
authors.initials: J
authors.lastname: Kahwaji
authors.affiliation: Transplant Immunotherapy Program, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: A
authors.initials: A
authors.lastname: Vo
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D050718:Complement C1 Inhibitor Protein / Q000627:therapeutic use; D051056:Complement Inactivating Agents / Q000627:therapeutic use*; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D016030:Kidney Transplantation; D014184:Transplantation, Homologous
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D050718:Complement C1 Inhibitor Protein; D051056:Complement Inactivating Agents; C481642:eculizumab