B Cell Depletion Is Not Required for Prolongation of Renal Allograft Survival in Non-Human Primates Using a Novel Anti-CD40 Blocking Antibody.

Abstract

CD40-CD154 pathway blockade significantly prolongs allograft survival in non-human primates (NHPs). However, antibodies targeting CD154, while efficacious, were associated with an increased incidence of thromboembolic complications precluding clinical development. Current antibodies targeting CD40 effectively prolong renal allograft survival in NHPs without associated thromboembolic events but with accompanying B cell depletion, raising the question of whether CD40 blockade or B cell depletion was the effective mechanism. We developed a novel, Fc-silent (i.e. incapable of antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity) anti-human CD40 monoclonal antibody (OM11-62MF). OM11 blocked recombinant CD154-mediated activation of leukocytes in vitro and inhibited T cell-dependent antibody responses in vivo in the absence of significant peripheral B cell depletion. We tested OM11 and an Fc-competent anti-CD40 antibody in MHC-mismatched cynomolgus monkey renal allograft transplantation as monotherapies. Allograft survival was significantly prolonged in animals dosed with the Fc-competent anti-CD40 antibody (52, 22, 24 days) in comparison to untreated monkeys (survival ˜ 7 days; n = 9). Well-functioning renal allografts survived up to 100 days in OM11-treated animals (100, 100, 100, 98, 78 days) at which point the experiment was terminated and graft morphology examined by histology. In contrast to good graft morphology in OM11-dosed group, acute cellular rejection was observed in animals treated with Fc-competent anti-CD40. Rapid and complete peripheral B cell depletion was only observed with the Fc-competent antibody, despite full peripheral CD40 receptor occupancy by both antibodies throughout the duration of the experiment. OM11 was well-tolerated and we observed no evidence of thromboembolic events. Collectively, our results indicated that CD40 pathway blockade in the absence of B cell depletion inhibited T cell-dependent immune responses and prevented allograft rejection. Thus, use of the Fc-silent anti-CD40 antibody OM11 appears to be an attractive approach for preventing solid organ transplant rejection and treating autoimmune diseases involving T cell-dependent humoral immune mechanisms. DISCLOSURES:Rush, J.: Employee, Novartis Pharmaceuticals Corporation. Cordoba, F.: Employee, Novartis Pharmaceuticals Corporation. Wieczorek, G.: Employee, Novartis Pharmaceuticals Corporation. Audet, M.: Employee, Novartis Pharmaceuticals Corporation. Schneider, M.: Employee, Novartis Pharmaceuticals Corporation. Patel, D.: Employee, Novartis Pharmaceuticals Corporation. Heusser, C.: Other, Novartis Pharmaceuticals Corporation, Contractor. Bruns, C.: Employee, Novartis Pharmaceuticals Corporation. Ulrich, P.: Employee, Novartis Pharmaceuticals Corporation. Slade, A.: Employee, Novartis Pharmaceuticals Corporation. Klupp, J.: Employee, Novartis Pharmaceuticals Corporation.