Session Time: 8:30am-9:45am
Presentation Time: 9:15am-9:30am
Location: Terrace Ballroom 1, 2, 3
Background. CD40-CD154 pathway blockade prolongs renal allograft survival in non-human primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications precluding clinical development. Current antibodies targeting CD40 effectively prolong renal allograft survival in NHPs but with accompanying B cell depletion, raising the question of whether CD40 blockade or B cell depletion was the effective mechanism.
Aim. To address this question, we developed a novel, human Fc-silent anti-CD40 monoclonal antibody (CFZ533) that was incapable of antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity and tested it alongside an Fc-competent, B-cell depleting version of the same antibody in MHC-mismatched cynomolgus monkey renal allograft transplantation.
Results. Allograft survival was prolonged in animals treated with the Fc-competent anti-CD40 antibody (52, 22, 24 days) in comparison to untreated monkeys (survival ∼ 7 days; n = 9). Well-functioning allografts survived up to 100 days in CFZ533-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 the CFZ533-dosed group, acute cellular rejection was observed in animals treated with Fc-competent anti-CD40. While both antibodies completely disrupted splenic germinal centers in transplanted animals, peripheral blood B-cell depletion was only observed with the Fc-competent antibody. CFZ533 was well-tolerated and there was no evidence of thromboembolic events. Additionally, in most animals CFZ533 largely suppressed a gene signature associated with acute rejection.
Conclusions. The data indicate that CD40 pathway blockade in the absence of B-cell depletion maintained very high allograft quality and function up to 100 days post-transplantation. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection and treating autoimmune diseases involving T-cell-dependent humoral immune mechanisms.
To cite this abstract in AMA style:Rush J, Wieczorek G, Audet M, Schneider M, Espie P, Roth L, Heusser C, Bruns C, Patel D, Cordoba F. A Novel, Blocking Anti-CD40 Monoclonal Antibody Prolongs Non-Human Primate Renal Allograft Survival in the Absence of B-Cell Depletion Or Thromboembolic Events [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/a-novel-blocking-anti-cd40-monoclonal-antibody-prolongs-non-human-primate-renal-allograft-survival-in-the-absence-of-b-cell-depletion-or-thromboembolic-events/. Accessed September 16, 2019.
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