The impact of IdeS (imlifidase) on allo-specific, xeno-reactive, and protective antibodies in a sensitized rhesus macaque model.

IF 3.3 4区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Xenotransplantation Pub Date : 2024-01-01 Epub Date: 2023-10-21 DOI:10.1111/xen.12833
Isabel DeLaura, Joanna Zikos, Imran J Anwar, Janghoon Yoon, Joseph Ladowski, Annette Jackson, Koen Van Rompay, Diogo Magnani, Stuart J Knechtle, Jean Kwun
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引用次数: 0

Abstract

Background: Highly sensitized patients face many barriers to kidney transplantation, including higher rates of antibody-mediated rejection after HLA-incompatible transplant. IdeS, an endopeptidase that cleaves IgG nonspecifically, has been trialed as desensitization prior to kidney transplant, and successfully cleaves donor-specific antibody (DSA), albeit with rebound.

Methods: IdeS was generated and tested (2 mg/kg, IV) in two naïve and four allosensitized nonhuman primates (NHP). Peripheral blood samples were collected at regular intervals following IdeS administration. Total IgG, total IgM, and anti-CMV antibodies were quantified with ELISA, and donor-specific antibody (DSA) and anti-pig antibodies were evaluated using flow cytometric crossmatch. B cell populations were assessed using flow cytometry.

Results: IdeS successfully cleaved rhesus IgG in vitro. In allosensitized NHP, robust reduction of total, DSA, anti-pig, and anti-CMV IgG was observed within one day following IdeS administration. Rapid rebound of all IgG antibody populations was observed, with antibody levels returning to baseline around day 14 post-infusion. Total IgM level was not affected by IdeS. Interestingly, a comparable reduction in antibody populations was observed after the second dose of IdeS. However, we have not observed any significant modulation of B cell subpopulations after IdeS.

Conclusions: This study evaluated efficacy of IdeS in the allosensitized NHP in IgG with various specificities, mirroring antibody kinetics in human patients. The efficacy of IdeS on preexisting anti-pig antibodies may be useful in clinical xenotransplantation. However, given the limitation of IdeS on its durability as a monotherapy, optimization of IdeS with other agents targeting the humoral response is further needed.

IdeS对致敏恒河猴模型中同种特异性、异种反应性和保护性抗体的影响。
背景:高度致敏患者在肾移植中面临许多障碍,包括HLA不相容移植后抗体介导的排斥反应发生率较高。IdeS是一种非特异性切割IgG的内肽酶,在肾移植前已被试验为脱敏,并成功切割供体特异性抗体(DSA),尽管有反弹。方法:在两种幼稚和四种同种致敏的非人灵长类动物(NHP)中产生并测试IdeS(2 mg/kg,IV)。IdeS给药后定期采集外周血样本。总IgG、总IgM和抗CMV抗体用ELISA进行定量,供体特异性抗体(DSA)和抗猪抗体用流式细胞术交叉配型进行评估。使用流式细胞术评估B细胞群。结果:IdeS在体外成功切割恒河猴IgG。在同种致敏的NHP中,在IdeS给药后一天内观察到总IgG、DSA、抗猪IgG和抗CMV IgG的显著降低。观察到所有IgG抗体群的快速反弹,抗体水平在输注后第14天左右恢复到基线。总IgM水平不受IdeS的影响。有趣的是,在第二剂IdeS后,观察到抗体群体的类似减少。然而,我们没有观察到IdeS对B细胞亚群的任何显著调节。结论:本研究评估了IdeS对具有各种特异性的同种异体致敏的IgG中的NHP的疗效,反映了人类患者的抗体动力学。IdeS对先前存在的抗猪抗体的疗效可能在临床异种移植中有用。然而,鉴于IdeS作为单一疗法的耐用性受到限制,还需要用其他靶向体液反应的药物优化IdeS。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Xenotransplantation
Xenotransplantation 医学-医学:研究与实验
CiteScore
6.80
自引率
15.40%
发文量
58
审稿时长
>12 weeks
期刊介绍: Xenotransplantation provides its readership with rapid communication of new findings in the field of organ and tissue transplantation across species barriers.The journal is not only of interest to those whose primary area is xenotransplantation, but also to veterinarians, microbiologists and geneticists. It also investigates and reports on the controversial theological, ethical, legal and psychological implications of xenotransplantation.
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