title: Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival.
abstract: In recent years, reagents have been developed that specifically target signals critical for effective T cell activation and function. Manipulation of the CD28/CD80/86 and CD40/CD154 pathways has exhibited extraordinary efficacy, particularly when the pathways are blocked simultaneously. Despite the reported efficacy of anti-CD154 in rodents and higher models, its future clinical use is uncertain due to reported thromboembolic events in clinical trials. To circumvent this potential complication, we developed and evaluated a chimeric Ab targeting CD40 (Chi220, BMS-224819) as an alternative to CD154. Although Chi220 blocks CD154 binding, it also possesses partial agonist properties and weak stimulatory potential. The anti-CD40 was tested alone and in combination with a rationally designed, high affinity variant of CTLA4-Ig, LEA29Y (belatacept), in a nonhuman primate model of islet transplantation. Although either agent alone only modestly prolonged islet survival (Chi220 alone: 14, 16, and 84 days; LEA29Y alone: 58 and 60 days), their combination (LEA29Y and Chi220) dramatically facilitated long term survival (237, 237, 220, >185, and 172 days). We found that the effects of Chi220 treatment were not mediated solely through deletion of CD20-bearing cells and that the combined therapy did not significantly impair established antiviral immunity.
authors.affiliation: Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Woodruff Memorial Research Building, 101 Woodruff Circle, Atlanta, GA 30322, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Adams
authors.forename: Nozomu
authors.initials: N
authors.lastname: Shirasugi
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Jones
authors.forename: Megan M
authors.initials: MM
authors.lastname: Durham
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Strobert
authors.forename: Shannon
authors.initials: S
authors.lastname: Cowan
authors.forename: Phyllis
authors.initials: P
authors.lastname: Rees
authors.forename: Rose
authors.initials: R
authors.lastname: Hendrix
authors.forename: Karen
authors.initials: K
authors.lastname: Price
authors.forename: Norma S
authors.initials: NS
authors.lastname: Kenyon
authors.forename: David
authors.initials: D
authors.lastname: Hagerty
authors.forename: Robert
authors.initials: R
authors.lastname: Townsend
authors.forename: Dianne
authors.initials: D
authors.lastname: Hollenbaugh
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Pearson
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D002460:Cell Line; D002678:Chimera; D004357:Drug Synergism; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000473:pathology; D008253:Macaca mulatta; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse