title: A novel monoclonal antibody to CD40 prolongs islet allograft survival.
abstract: The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well-documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti-CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell-dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC-mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile.
authors: Emory Transplant Center, Department of Surgery, Emory University, Atlanta, GA, USA.
authors: M
authors: M
authors: Lowe
authors: I R
authors: IR
authors: Badell
authors: P
authors: P
authors: Thompson
authors: B
authors: B
authors: Martin
authors: F
authors: F
authors: Leopardi
authors: E
authors: E
authors: Strobert
authors: A A
authors: AA
authors: Price
authors: H S
authors: HS
authors: Abdulkerim
authors: R
authors: R
authors: Wang
authors: N N
authors: NN
authors: Iwakoshi
authors: A B
authors: AB
authors: Adams
authors: A D
authors: AD
authors: Kirk
authors: C P
authors: CP
authors: Larsen
authors: K A
authors: KA
authors: Reimann
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000917:Antibody Formation; D019013:CD40 Antigens / Q000276:immunology*; D006085:Graft Survival; D006801:Humans; D016381:Islets of Langerhans Transplantation; D008253:Macaca mulatta
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens