Departments of Medicine and Surgery, University of California San Francisco, San Francisco, California.
Department of Nephrology and Kidney Transplantation, University Hospital Vall d'Hebron, Barcelona, Spain.
J Am Soc Nephrol. 2024 Mar 1;35(3):347-360. doi: 10.1681/ASN.0000000000000287. Epub 2023 Dec 26.
There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist.
Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization.
This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively.
Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted.
In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity.
NCT04294459 .
目前尚无针对肾移植候选者的标准化脱敏方案。浆细胞表达的 CD38 可作为脱敏的靶点，以耗尽产生同种异体抗体和供体特异性抗体的浆细胞。目前关于 CD38 抗体在等待肾移植的患者中用于脱敏的研究和病例报告较少。本研究表明，CD38 靶向治疗药物伊沙妥昔单抗在肾移植候选者中耐受性良好，可持久降低抗 HLA 抗体并具有部分脱敏活性。本研究的短期治疗期和长期随访使我们能够了解任何抗体反弹的机制和时间。伊沙妥昔单抗可能作为现有脱敏治疗的辅助治疗选择，用于肾移植等待名单上的患者。
计算的 panel reactive antibody（cPRA）≥80.00%的患者，特别是 cPRA≥99.90%的患者，被认为是高度致敏的，并且未被肾脏分配系统所服务。脱敏通过消除循环中的反应性抗体和/或抑制抗体产生来增加负交叉匹配的机会。CD38 在浆细胞上高度表达，因此是脱敏的潜在靶点。
这是一项开放标签的单臂 1/2 期研究，旨在研究伊沙妥昔单抗在等待肾移植的患者中的安全性、药代动力学和初步疗效。有两个队列，队列 A 和 B，分别招募 cPRA≥99.90%和 80.00%至<99.90%的患者。
23 名患者（12 名队列 A，11 名队列 B）接受每周 10mg/kg 的伊沙妥昔单抗治疗 4 周，然后每 2 周治疗 8 周。伊沙妥昔单抗耐受性良好，药代动力学和药效学特征表明与多发性骨髓瘤试验相似的暴露情况。它导致 CD38+浆母细胞、浆细胞和 NK 细胞减少，以及 HLA 特异性 IgG 产生的记忆 B 细胞显著减少。基于预先确定的复合脱敏终点，队列 A 和 B 的总体缓解率分别为 83.3%和 81.8%。大多数应答者的抗 HLA 抗体下降，且在最后一次给药后 26 周仍保持下降。总体而言，cPRA 值受影响较小，但是只有 23 名患者中的 9 名（39%）cPRA 值降至目标水平。截至研究截止日期（中位随访 68 周），有 6 名患者收到了移植要约，其中 4 名接受了要约。
在这项开放标签试验中，伊沙妥昔单抗耐受性良好，可持久降低抗 HLA 抗体并具有部分脱敏活性。
NCT04294459。
