基于达雷妥尤单抗的肾移植前脱敏开放标签1/2期研究
Open-Label Phase 1/2 Study of Daratumumab-Based Desensitization Before Kidney Transplantation.
作者信息
Pilon Caroline, Joher Nizar, Usureau Cédric, Boutin Emmanuelle, Boueilh Anna, Taupin Jean-Luc, Thiolat Allan, Cohen José L, Kheav Vissal David, Canoui-Poitrine Florence, Carmagnat Maryvonnick, Grimbert Philippe, Matignon Marie
机构信息
Universite Paris Est Creteil, INSERM IMRB U955, Créteil, France.
Assistance Publique-Hôpitaux de Paris, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biotherapy, Fédération hospitalo-Universitaire, Innovative therapy for immune disorders, Créteil, France.
出版信息
Kidney Int Rep. 2024 Aug 26;9(11):3250-3264. doi: 10.1016/j.ekir.2024.08.020. eCollection 2024 Nov.
INTRODUCTION
The safety and benefit of the anti-CD38 monoclonal antibody daratumumab, which induces lysis of antibody-producing plasma cells in sensitized patients prior to kidney transplantation, remain to be determined.
METHODS
A 2-phase (1 and 2), monocentric open-label study was conducted to evaluate the month 6 (M6) safety and efficacy of daratumumab in kidney transplant candidates with calculated panel reactive antibody (cPRA) > 95%. In the first (safety) phase, we used 4-weekly escalating doses of daratumumab. Phase 2 tested desensitization with 8 weekly infusions of 16 mg/kg daratumumab. cPRA 10,000 was calculated considering only human leukocyte antigen (HLA) antibodies with mean fluorescence intensity (MFI) of > 10,000.
RESULTS
Nine patients were enrolled in phase 1 and 14 in phase 2. Safety analysis showed 4 serious non-treatment-emergent adverse events (non-TEAEs), 36 mild TEAEs, mostly infusion-related reactions, grade 1 and 2 (causing 2 temporary drug discontinuations), but no serious TEAEs. Significant reductions in anti-HLA antibodies were observed at month 3 (M3), with cPRA 10,000 ( = 0.003), number of anti-HLA ( < 0.001), maximum MFI (MFI max) ( = 0.053), and the sum of MFI (MFI sum) ( < 0.001), with complete return to baseline levels at month 12 (M12). At M6, 46.15% (19.22%-74.87%) and 76.92% (46.19%-94.96%) of patients showed sustained response (1% decrease in cPRA) for cPRA 2000 and 10,000, respectively. At month 1 (M1), immune cells (T-reg, CD8 + TEMRA, CD19 + CD138 + B cells, and NK cells) significantly decreased. At M3, other antibodies decreased significantly, but returned to baseline levels at M12, except for gamma globulins, without any infectious complications.
CONCLUSION
The first use of daratumumab in desensitization demonstrated infusion-related adverse (AEs) events and rapid, albeit transient, reductions in anti-HLA antibodies, with less than 40% of durable responders, limiting its potential clinical use.
引言
抗CD38单克隆抗体达雷妥尤单抗可诱导致敏患者肾移植前产生抗体的浆细胞裂解，其安全性和益处仍有待确定。
方法
开展了一项2期（1期和2期）单中心开放标签研究，以评估达雷妥尤单抗在计算的群体反应性抗体（cPRA）>95%的肾移植候选受者中第6个月（M6）的安全性和疗效。在第一阶段（安全性阶段），我们使用了每4周递增剂量的达雷妥尤单抗。2期测试了每周1次、共8次输注16mg/kg达雷妥尤单抗的脱敏方案。仅考虑平均荧光强度（MFI）>10,000的人类白细胞抗原（HLA）抗体来计算cPRA≥10,000。
结果
1期纳入9例患者，2期纳入14例患者。安全性分析显示有4例严重的非治疗引起的不良事件（非TEAE），36例轻度TEAE，大多为输注相关反应，1级和2级（导致2例暂时停药），但无严重TEAE。在第3个月（M3）观察到抗HLA抗体显著降低，cPRA≥10,000（P=0.003）、抗HLA数量（P<0.001）、最大MFI（MFI max）（P=0.053）和MFI总和（MFI sum）（P<0.001）均降低，在第12个月（M12）完全恢复至基线水平。在M6时，cPRA≥2000和cPRA≥10,000的患者分别有46.15%（19.22%-74.87%）和76.92%（46.19%-94.96%）显示出持续反应（cPRA降低1%）。在第1个月（M1），免疫细胞（调节性T细胞、CD8+终末分化记忆性T细胞、CD19+CD138+B细胞和自然杀伤细胞）显著减少。在M3时，其他抗体显著降低，但除γ球蛋白外，在M12时恢复至基线水平，且无任何感染并发症。
结论
达雷妥尤单抗首次用于脱敏显示出与输注相关的不良事件以及抗HLA抗体迅速（尽管是短暂的）降低，持久反应者不到40%，限制了其潜在的临床应用。
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