Terminal Complement Inhibition Decreases Antibody-Mediated Rejection in Sensitized Renal Transplant Recipients

Abstract

Sensitized renal transplant recipients with high levels of donor-specific alloantibody (DSA) commonly develop antibody-mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti-C5 antibody, eculizumab, in the prevention AMR in renal transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy-proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)-based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1-year protocol biopsy, transplant glomerulopathy was found to be present in 6.7% (1/15) eculizumab-treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal transplant recipients (ClincalTrials.gov number NCT006707).

Effect of the Anti-C1s Humanized Antibody TNT009 and Its Parental Mouse Variant TNT003 on HLA Antibody–Induced Complement Activation—A Preclinical In Vitro Study

“…Our finding of profound and specific in vitro blockade of the classic complement cascade by humanized mAb TNT009 provides a foundation for its further evaluation in clinical transplantation. Indeed, in recent years, the concept of complement inhibition as a strategy to counteract AMR has gained increasing interest, and the first human trials evaluating complement inhibitors, such as C1‐INH or eculizumab (11, 13, 17, 18, 19, 31), have provided some evidence for clinical efficacy. One may speculate that the CP‐specific mode of action of TNT009 could be beneficial in terms of preserved immunity, because it leaves other complement pathways, such as the lectin pathway, intact.…”

HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

“…Its prevalence in indication biopsies varies from 1.6% to 7% (5,6,(11)(12)(13). Currently, no treatment is available to reverse, or even mitigate, the effects of TG (14)(15)(16)(17). Considering the absence of effective therapy, the implications of allograft failure and the scarcity of organs available for transplantation, it is important to prevent the development of TG in KTR.…”

Eculizumab Prevents Recurrent Antiphospholipid Antibody Syndrome and Enables Successful Renal Transplantation

“…As a result, they can be highly sensitized. Eculizumab has previously been shown to provide additional protection against antibody-mediated rejection after desensitization (26). Since the pathogenesis of APS-and HLA-antibody-mediated rejection overlap and control of humoral responses is paramount to effective therapy for both diseases, it has been intriguing to consider prevention of both conditions with a single therapeutic cocktail.…”

“…In renal transplant recipients, it has been used for the treatment of a variety of complement/ antibody-mediated microangiopathy syndromes including aHUS (24,25) and antibody-mediated rejection (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) and in single case studies of patients with CAPS (13) and APS (27).…”