Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study

Abstract

Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

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.…”

Antibody-mediated rejection: New approaches in prevention and management

“…Shows depletion of endogenous C1-INH activity by plasmapheresis in a randomized, doubleblind, placebo-controlled pilot study of C1-INH (Cinryze) in acute AMR. From Montgomery RA et al 87 . AMR, antibodymediated rejection; C1-INH, C1 esterase inhibitor; SD, standard deviation As clinically apparent chronic renal allograft injury and long-term graft loss due to AMR is a relatively infrequent event among the general transplant population and may take several years to manifest, prospective randomized clinical trials required to assess the benefits of therapeutic intervention require large sample sizes that are hard to accrue, long time frames, and great expense.…”

Plasmapheresis Therapy in Kidney Transplant Rejection

“…After transplantation early monitoring and treatment of AMR are fundamental to preserve the renal function and graft. A significant survival benefit was seen in 1025 HLAsensitized patients who underwent desensitization before receiving a KT from a living donor [33].…”

“…The antibody burden may exceed the capacity of TPE to control it, allowing antibodies to bind to the endothelium of renal microvasculature and activate complement [33]. Gubensek et al [34], Gubensek et al [35], and Brown et al [36] had reported the long-term experience of intensive treatment as A rescue therapy for AMR in KT.…”

“…The higher costs associated with the use of IA indicated its use in high-risk populations (i.e., hyperimmune or ABO-I patients, pretransplant cross-match positivity, AAMR (acute AMR). In a randomized double-blind placebo-controlled study by Montgomery et al [33], 18 patients have ongoing C1 INH consumption, the goal was to aim for twice physiological C1 INH levels by dosing patients with an intravenous infusion of 5,000 U C1 INH (maximum of 100 U/ kg) or placebo on day 1 after the diagnosis of AMR, followed by 2,500 U C1 INH (maximum of 50 U/kg) or placebo on days 3, 5, 7, 9, 11, and 13. However, there were no discontinuations, graft losses, deaths, or study drugrelated serious adverse events.…”