title: Long-term hepatic allograft acceptance based on CD40 blockade by ASKP1240 in nonhuman primates.
abstract: Blockade of the CD40-CD154 costimulatory signal is an attractive strategy for immunosuppression and tolerance induction in organ transplantation. Treatment with anti-CD154 monoclonal antibodies (mAbs) results in potent immunosuppression in nonhuman primates (NHPs). Despite plans for future clinical use, further development of these treatments was halted by complications. As an alternative approach, we have been focusing on the inhibition of the counter receptor, CD40 and have shown that a novel human anti-CD40 mAb, ASKP1240, markedly prolongs renal allograft survival in NHPs, although allografts eventually underwent chronic allograft nephropathy. On the basis of our previous findings that a CD40-CD154 costimulation blockade induces tolerance to hepatic, but not cardiac, allografts in rodents, we tested here our hypothesis that a blockade of CD40 by ASKP1240 allows acceptance of hepatic allografts in NHPs. A 2-week ASKP1240 induction treatment prolonged liver allograft survival in NHPs; however, the graft function deteriorated due to chronic rejection. In contrast, a 6-month ASKP1240 maintenance monotherapy efficiently suppressed both cellular and humoral alloimmune responses and prevented rejection on the hepatic allograft. No serious side effects, including thromboembolic complications, were noted in the ASKP1240-treated monkeys. We conclude that CD40 blockade by ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.
authors.affiliation: Department of General Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Oura
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: D
authors.initials: D
authors.lastname: Fukumori
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: G
authors.initials: G
authors.lastname: Hirokata
authors.forename: K
authors.initials: K
authors.lastname: Wakayama
authors.forename: M
authors.initials: M
authors.lastname: Taniguchi
authors.forename: T
authors.initials: T
authors.lastname: Shimamura
authors.forename: T
authors.initials: T
authors.lastname: Miura
authors.forename: K
authors.initials: K
authors.lastname: Okimura
authors.forename: K
authors.initials: K
authors.lastname: Maeta
authors.forename: H
authors.initials: H
authors.lastname: Haga
authors.forename: K
authors.initials: K
authors.lastname: Kubota
authors.forename: A
authors.initials: A
authors.lastname: Shimizu
authors.forename: F
authors.initials: F
authors.lastname: Sakai
authors.forename: H
authors.initials: H
authors.lastname: Furukawa
authors.forename: S
authors.initials: S
authors.lastname: Todo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016031:Liver Transplantation; D007959:Lymphocyte Culture Test, Mixed; D008252:Macaca fascicularis; D008297:Male; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens; C586087:bleselumab