奥地利维也纳医科大学Georg A. Böhmig团队研究了菲泽妥单抗治疗抗体介导的排异反应的随机2期试验。该研究于2024年5月25日发表于《新英格兰医学杂志》。

抗体介导的排异反应是肾移植失败的主要原因。靶向CD38以抑制同种异体抗体和自然杀伤（NK）细胞引起的移植物损伤可能是一种治疗选择。

在这项临床2期、双盲、随机、安慰剂对照试验中，研究组将移植后至少180天出现抗体介导的排异反应的患者分为9次输注CD38单克隆抗体菲泽妥单抗（剂量为每公斤体重16 mg）或安慰剂，为期6个月，然后是6个月的观察期。主要结局是菲泽妥单抗的安全性和副作用。关键次要结局是24周和52周的肾活检结果、供体特异性抗体水平、外周NK细胞计数和供体来源的无细胞DNA水平。

共有22名患者接受了随机分组（11名接受菲泽妥单抗治疗，11名接受安慰剂治疗）。从移植到纳入试验的中位时间为9年。菲泽妥单抗组有8名患者出现轻度或中度输液反应。菲泽妥单抗组1名患者和安慰剂组4名患者发生严重不良事件；安慰剂组有1例患者出现移植物丢失。第24周后，菲泽妥单抗组（11名患者中有9名[82%]）比安慰剂组（10名患者中的2名[20%]）更频繁地解决形态抗体介导的排异反应，差异为62个百分点（95%置信区间[CI]，19比100），风险比为0.23（95%可信区间[CI]0.06比0.83）。菲泽妥单抗组的中位微血管炎症评分低于安慰剂组（0比2.5），平均差异为−1.95（95%CI，−2.97比−0.92）。反映抗体介导的排异反应概率（0.17对0.77）和供体来源的无细胞DNA水平（0.31%对0.82%）的分子评分亦显著低于安慰剂组。在第52周，据报道，对菲泽妥单抗有反应的9名患者中有3名再次发生抗体介导的排异反应，分子活性和生物标志物水平向基线水平增加。

研究结果表明，菲泽妥单抗在抗体介导的排异反应患者中具有可接受的安全性和副作用。

附：英文原文

Title: A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection

Author: Katharina A. Mayer, Eva Schrezenmeier, Matthias Diebold, Philip F. Halloran, Martina Schatzl, Sabine Schranz, Susanne Haindl, Silke Kasbohm, Alexander Kainz, Farsad Eskandary, Konstantin Doberer, Uptal D. Patel, Jaideep S. Dudani, Heinz Regele, Nicolas Kozakowski, Johannes Klger, Rainer Boxhammer, Kerstin Amann, Elisabeth Puchhammer-Stckl, Hannes Vietzen, Julia Beck, Ekkehard Schütz, Aylin Akifova, Christa Firbas, Houston N. Gilbert, Bilgin Osmanodja, Fabian Halleck, Bernd Jilma, Klemens Budde, Georg A. Bhmig

Issue&Volume: 2024-05-25

Abstract:

BACKGROUND

Antibody-mediated rejection is a leading cause of kidney-transplant failure. The targeting of CD38 to inhibit graft injury caused by alloantibodies and natural killer (NK) cells may be a therapeutic option.

METHODS

In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with antibody-mediated rejection that had occurred at least 180 days after transplantation to receive nine infusions of the CD38 monoclonal antibody felzartamab (at a dose of 16 mg per kilogram of body weight) or placebo for 6 months, followed by a 6-month observation period. The primary outcome was the safety and side-effect profile of felzartamab. Key secondary outcomes were renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels.

RESULTS

A total of 22 patients underwent randomization (11 to receive felzartamab and 11 to receive placebo). The median time from transplantation until trial inclusion was 9 years. Mild or moderate infusion reactions occurred in 8 patients in the felzartamab group. Serious adverse events occurred in 1 patient in the felzartamab group and in 4 patients in the placebo group; graft loss occurred in 1 patient in the placebo group. After week 24, resolution of morphologic antibody-mediated rejection was more frequent with felzartamab (in 9 of 11 patients [82%]) than with placebo (in 2 of 10 patients [20%]), for a difference of 62 percentage points (95% confidence interval [CI], 19 to 100) and a risk ratio of 0.23 (95% confidence interval [CI], 0.06 to 0.83). The median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5), for a mean difference of 1.95 (95% CI, 2.97 to 0.92). Also lower was a molecular score reflecting the probability of antibody-mediated rejection (0.17 vs. 0.77) and the level of donor-derived cell-free DNA (0.31% vs. 0.82%). At week 52, the recurrence of antibody-mediated rejection was reported in 3 of 9 patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels.

CONCLUSIONS

Felzartamab had acceptable safety and side-effect profiles in patients with antibody-mediated rejection.

DOI: NJ202405250000002

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2400763