High human leukocyte antigen (HLA) sensitization limits access to compatible transplantation. New CD38-targeting agents have been shown to reduce anti-HLA antibodies, although with important interpatient variability. Thus, pretreatment identification of responder and nonresponder (NR) patients is needed for treatment decision-making. We analyzed 26 highly sensitized (HS) patients from 2 desensitization trials using anti-CD38 monoclonal antibodies. Hierarchical clustering identified 3 serologic responder groups: high responders, low responders, and NR. Spectral flow cytometry and functional HLA-specific memory B cell (mBC) assessment were first conducted on peripheral blood mononuclear cells and bone marrow samples from 16 patients treated with isatuximab (NCT04294459). Isatuximab effectively depleted bone marrow plasma cells, peripheral CD38-expressing plasmablasts, plasma cells, transitional B cells, and class-switch mBCs, ultimately reducing frequencies of HLA-specific immunoglobulin G (IgG)-producing mBCs. Multidimensional spectral flow cytometry with partial least squares discriminant analysis revealed that pretreatment abundance of specific circulating mBC phenotypes, especially CD38neg class-switch mBCs, accurately distinguished between high serologic responders and low responders or NR (AUC 0.958, 0.860-1.000, P = .009), who also displayed significantly lower frequencies of HLA-specific IgG-producing mBCs (P < .0001). This phenotypical mBC signature predicting response to therapy was validated in an external HS patient cohort (n = 10) receiving daratumumab (NCT04204980). This study identifies critical circulating mBC subset phenotypes that distinguish HS patients with successful serologic responses to CD38-targeting desensitization therapies, potentially guiding treatment decision-making.

中文翻译：

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在高度致敏的肾移植候选者中，外周记忆 B 细胞会挑战靶向 CD38 脱敏治疗的抗 HLA 血清学反应


高人类白细胞抗原 （HLA） 致敏性限制了相容移植的可及性。新的 CD38 靶向药物已被证明可以减少抗 HLA 抗体，尽管患者间存在很大的差异。因此，治疗前需要识别反应者和无反应者 （NR） 患者，以便做出治疗决策。我们分析了来自 2 项使用抗 CD38 单克隆抗体的脱敏试验的 26 例高度致敏 （HS） 患者。分层聚类确定了 3 个血清学反应者组：高反应者、低反应者和 NR。首先对 16 例接受 isatuximab （NCT04294459） 治疗的患者的外周血单核细胞和骨髓样本进行光谱流式细胞术和功能性 HLA 特异性记忆 B 细胞 （mBC） 评估。Isatuximab 有效消耗骨髓浆细胞、表达外周 CD38 的浆母细胞、浆细胞、过渡 B 细胞和类别转换 mBCs，最终降低产生 HLA 特异性免疫球蛋白 G （IgG） 的 mBCs 的频率。具有偏最小二乘判别分析的多维光谱流式细胞术显示，特异性循环 mBC 表型的治疗前丰度，尤其是 CD38neg 类别转换 mBCs，准确区分了高血清学反应者和低反应者或 NR （AUC 0.958， 0.860-1.000， P = .009），后者也显示出显着较低的 HLA 特异性 IgG 产生 mBCs 的频率 （P < .0001）。这种预测治疗反应的表型 mBC 特征在接受 daratumumab （NCT04204980） 的外部 HS 患者队列 （n = 10） 中得到了验证。 本研究确定了关键的循环 mBC 亚群表型，这些表型区分了对 CD38 靶向脱敏治疗成功血清学反应的 HS 患者，可能指导治疗决策。