Jordan Stanley C, Kucher Klaus, Bagger Morten, Hockey Hans-Ulrich, Wagner Kristina, Ammerman Noriko, Vo Ashley
Comprehensive Transplant Center, Transplant Immunotherapy Program Cedars-Sinai Medical Center, Los Angeles, California, USA.
Novartis Institutes for BioMedical Research, Basel, Switzerland.
Am J Transplant. 2020 Sep;20(9):2581-2588. doi: 10.1111/ajt.15922. Epub 2020 May 13.
Awareness of drug-drug interactions is critical in organ transplant recipient management. However, biologic agents interfering with monoclonal antibodies is not widely considered. We report the effect of high-dose intravenous immunoglobulin (IVIg) on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the human anti-C5 monoclonal antibody tesidolumab (LFG316) in end-stage renal disease patients awaiting kidney transplant. In this single-center, phase 1, open-label, parallel-group study, 8 patients were assigned to receive either single-dose tesidolumab + IVIg or tesidolumab alone, with 56-day follow-up. Within-group PK parameters were consistent. Mean tesidolumab exposure decreased 34%, clearance increased 63%, and half-life decreased 41% comparing tesidolumab + IVIg to tesidolumab alone. IVIg influence on tesidolumab elimination was most evident in the first 3 weeks. Complete suppression of both total and alternative complement activities was maintained for 4 weeks in the tesidolumab alone group and for 2 weeks in the tesidolumab + IVIg group. Tesidolumab was well tolerated. IVIg infused before tesidolumab affected tesidolumab PK and PD, resulting in a shortened period of full complement activity inhibition. These findings suggest a clinically relevant impact of IVIg on monoclonal antibody clearance and indirectly hint at an IVIg mechanism of action in treating autoimmune diseases and allosensitization by accelerating pathogenic IgG antibody degradation. Trial registration number: NCT02878616.
了解药物相互作用在器官移植受者管理中至关重要。然而，干扰单克隆抗体的生物制剂尚未得到广泛关注。我们报告了大剂量静脉注射免疫球蛋白（IVIg）对等待肾移植的终末期肾病患者使用的人抗C5单克隆抗体tesidolumab（LFG316）的安全性、耐受性、药代动力学（PK）和药效学（PD）的影响。在这项单中心、1期、开放标签、平行组研究中，8名患者被分配接受单剂量tesidolumab + IVIg或单独使用tesidolumab，并进行56天随访。组内PK参数一致。与单独使用tesidolumab相比，tesidolumab + IVIg组的平均tesidolumab暴露量降低了34%，清除率增加了63%，半衰期缩短了41%。IVIg对tesidolumab消除的影响在最初3周最为明显。单独使用tesidolumab组的总补体活性和替代补体活性完全抑制维持了4周，而tesidolumab + IVIg组维持了2周。Tesidolumab耐受性良好。在tesidolumab之前输注IVIg会影响tesidolumab的PK和PD，导致完全补体活性抑制期缩短。这些发现表明IVIg对单克隆抗体清除具有临床相关影响，并间接提示了IVIg在治疗自身免疫性疾病和通过加速致病性IgG抗体降解进行同种致敏中的作用机制。试验注册号：NCT02878616。
