Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany.
J Am Soc Nephrol. 2021 Mar;32(3):708-722. doi: 10.1681/ASN.2020071106. Epub 2020 Dec 18.
Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy.
We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab.
Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m per month, respectively, =0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab.
Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.
晚期抗体介导的排斥反应（ABMR）是移植失败的主要原因。阻断白细胞介素 6（IL-6）已被提议作为一种有前途的治疗策略。
我们进行了一项 2 期随机试验，以评估抗 IL-6 抗体克拉扎珠单抗在晚期 ABMR 中的安全性（主要终点）和疗效（次要终点分析）。该试验纳入了 20 名肾移植受者，这些受者在移植后≥365 天出现供体特异性、抗体阳性的 ABMR。患者按 1:1 随机接受 25 mg 克拉扎珠单抗或安慰剂（每 4 周皮下注射）12 周（A 部分），随后进行 40 周开放标签扩展（B 部分），在此期间所有患者均接受克拉扎珠单抗治疗。
5 名（25%）接受活性治疗的患者发生了严重感染事件，2 名（10%）发生了憩室疾病并发症，导致试验退出。接受克拉扎珠单抗治疗的患者的供体特异性抗体明显下降，并且在延长治疗过程中，调节了与排斥反应相关的基因表达模式。在 18 名患者中，51 周时的移植肾活检显示，7 名（38.9%）患者的分子 ABMR 评分阴性，5 名（27.8%）患者的毛细血管 C4d 沉积消失，4 名（22.2%）患者的形态学 ABMR 活动消退。尽管蛋白尿保持稳定，但与安慰剂相比，克拉扎珠单抗在 A 部分期间 eGFR 下降速度较慢（-0.96；95%置信区间[95%CI]，-1.96 至 0.03 与-2.43；95%CI，-3.40 至-1.46 ml/min/1.73 m/月，分别为 0.04）。在 B 部分期间，从安慰剂转换为克拉扎珠单抗的患者的 eGFR 下降斜率改善，并且与最初分配给克拉扎珠单抗的患者不再有显著差异。
尽管安全性数据表明需要仔细选择和监测患者，但我们的初步疗效结果表明克拉扎珠单抗对 ABMR 活性和进展可能具有有益作用。
