A Novel Monoclonal Antibody to CD40 Prolongs Islet Allograft Survival

• Type of Material: Article
• Authors: Michael Charles Lowe, Emory University; Idelberto R. Badell, Emory University; P. Thompson, Emory University; B. Martin, Emory University; F. Leopardi, Emory University; Elizabeth Strobert, Emory University; A.A. Price, Harvard Medical School; H.S. Abdulkerim, Harvard Medical School; R. Wang, Harvard Medical School; Neal N. Iwakoshi, Emory University; A.B. Adams, Emory University; Allan D Kirk, Emory University; Christian P Larsen, Emory University; K.A. Reimann, Harvard Medical School
• Language: English
• Date: 2012-08
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 The American Society of Transplantation and the American Society of Transplant Surgeons
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 12
• Issue: 8
• Start Page: 2079
• End Page: 2087
• Grant/Funding Information: Juvenile Diabetes Research Foundation 4-2005-1328, NIAID contract HHSN 272200900037C, RR016001, NIH/National Center for Research Resources P51 RR000165-51
• Keywords: Type 1 Diabetes Mellitus; Co-stimulation Blockade; Islet Transplantation; Immunosuppressive therapy
• Research Categories: Health Sciences, Medicine and Surgery

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.