A Novel, Blocking, Fc-Silent Anti-CD40 Monoclonal Antibody Prolongs Nonhuman Primate Renal Allograft Survival in the Absence of B Cell Depletion

Abstract

y Both authors contributed equally.CD40-CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHCmismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98-100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was welltolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection.

Autoimmune manifestations in aged mice arise from early-life immune dysregulation

“…New strategies are being developed to avoid platelet aggregation, such as monovalent anti-CD40L antibodies (76), CD40L antagonist scaffolds engineered to avoid FcR binding (ClinicalTrials.gov Identifier: NCT02151110), or antibodies to CD40 such as ASKP1240 (77) (ClinicalTrials.gov Identifier: NCT01780844, NCT01585233), or the Fc-silent anti-CD40 antibody CFZ533 (78) that is currently in clinical trial for pSS (ClinicalTrials.gov Identifier: NCT02291029), RA (ClinicalTrials.gov Identifier: NCT02089087), as well as several other indications. The ability of prophylactic anti-CD40L to dissolve germinal centers and halt autoimmune humoral responses in our studies, suggests biologics that target CD40/CD40L interaction may have efficacy in diseases that are predated by the appearance of autoantibodies.…”

Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases

“…MEDI4920, a Tn3-fusion protein with reactivity to CD40L, is currently in phase I safety trials. Additionally, antagonist and/or depleting antibodies against CD40 have been produced (ch5D12, chi220–BMS-224819, ASKP1240, FFP104, CFZ533), with encouraging preclinical results 51 , and some of them are being tested in phase I–II trials in Sjögren syndrome 52 , RA 53 and other autoimmune conditions (TABLE 1). If these strategies can overcome the adverse effects associated with agents that block CD40-C40L interactions, such agents are an attractive avenue, and the possibility for clinical benefit in rheumatic diseases is high.…”

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

“…Fc-silent forms of anti-CD40 (CFZ533) [82, 83] and anti-CD40L (BMS-986004) [84] antibodies, which lack the side effects of the respective full-length antibodies (B lymphopenia and thromboembolic events), are currently being developed for clinical applications in transplantation. Growing evidence suggests that costimulation through CD40L is highly dispensable in human Tregs, in contrast to conventional T cells, and that CD40/CD40L blockade may tip the balance toward suppression.…”