Strategies to Optimize Pig-to Primate Kidney Xenograft Survival

优化猪到灵长类肾脏异种移植物存活的策略

• 批准号: 10402757
• 负责人: Andrew B Adams
• 金额: $ 144.28万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402757
• 关键词: Address; American; Animals; Anti-CD40; Antibodies; Antibody Therapy; Antibody titer measurement; Antigens; Binding; CD4 Positive T Lymphocytes; Carbohydrates; Cell surface; Clinic; Clinical; Clinical Trials; Complement; Data; Development; Enzymes; FDA approved; Failure; Family suidae; Future; Genes; Genetic Engineering; Genome engineering; Human; Immune; Immune response; Immunity; Immunoglobulin G; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Individual; Injury; Kidney; Kidney Transplantation; Knock-out; Life; Long-Term Survivors; Mediating; Mutation; Organ; Organ Donor; Pathway interactions; Patients; Polysaccharides; Population; Positioning Attribute; Pre-Clinical Model; Prevention; Primates; Proteasome Inhibition; Proteins; Protocols documentation; Reagent; Reporting; Role; Savings; Source; TNFRSF5 gene; TNFSF5 gene; Techniques; Technology; Testing; Tissue Donors; Tissues; Transferase; Transplantation; Wait Time; Waiting Lists; Work; Xenograft Model; Xenograft procedure; antagonist; antibody-mediated rejection; base; clinical application; clinical translation; clinically relevant; desensitization; genome editing; innovation; kidney xenograft; nonhuman primate; novel; prevent; species difference; success; transplant model

With over 100,000 patients now on the waiting list for a kidney transplant, it is obvious that there is a critical shortage of available donor organs. Xenotransplantation represents a promising solution. While pigs are viewed as the optimal non-human source of organs, the potency of the human immune response to pig organs has prevented the clinical application of pig-to-human kidney transplantation. In this application we propose using cutting-edge genetic engineering approaches in combination with novel, clinically relevant immune- suppressants to reduce both the humoral and cellular immune response of nonhuman primates undergoing kidney xenotransplantation as a preclinical model to inform future human trials. With recent advances in genome editing techniques we and others have created novel pig donors with multiple genetic alterations and resultant improvements in xenograft survival. In addition, we have developed and applied strategies to avoid early antibody mediated rejection by using a pre-transplant antibody screen similar to the crossmatch used in clinical transplantation. We further identified CD4+ T cells as a critical subset in xenograft rejection and demonstrated consistent long-term survival in the pig-to-primate kidney transplant model. These results represent a major advance on the road to clinical translation of xenotransplantation. Here we propose to study three major barriers to the clinical translation of xenotransplantation: (1) All long-term xenograft survival has been dependent on antibody blockade of the CD40-CD154 pathway and there is currently no clinically approved reagent. We will evaluate the only two clinically relevant CD40-CD154 pathway antagonists that are in development and have shown efficacy in human patients: a) Iscalimab, a novel anti-CD40 antibody and b) VIB4920, an innovative CD154-targeting protein. Neither of these new reagents has been tested in xenotransplantation previously. (2) We will determine the impact of two novel desensitization treatments as well as transient complement inhibition on early antibody mediated rejection. We will test imlifidase (IdeS, an IgG degrading enzyme recently approved by the FDA for the prevention and treatment of antibody mediated rejection) as well as an innovative desensitization strategy combining costimulation blockade and proteasome inhibition. In addition to addressing early antibody mediated injury we will test a novel complement-directed therapy, tesidolumab, an anti-C5 antibody that is currently being evaluated in clinical trials. We present exciting data using the novel anti-C5 antibody tesidolumab, suggesting that targeted complement inhibition mitigates early antibody rejection. (3) Lastly we will address the important issue of late antibody mediated injury. Given our success we are uniquely positioned to study this important problem. Similar to clinical kidney transplantation, we have new data that late kidney xenograft injury is directly related to the development of anti-SLA class II antibody. We will test the importance of this finding by deleting the genes for SLA class II DQ and DR in the porcine donor tissue and assessing the impact on rejection and protective immunity.

现在有超过 100,000 名患者在等待肾移植的名单上，显然存在一个关键的问题 可用的捐赠器官短缺。异种移植是一种有前途的解决方案。虽然猪是 被视为最佳的非人类器官来源，人类对猪器官的免疫反应的效力 阻碍了猪肾移植的临床应用。在此应用中，我们建议 使用尖端的基因工程方法结合新颖的、临床相关的免疫 抑制剂可减少非人类灵长类动物的体液和细胞免疫反应 肾异种移植作为临床前模型，为未来的人体试验提供信息。随着最近的进展 我们和其他人利用基因组编辑技术创造了具有多种基因改变的新型猪捐赠者， 从而提高异种移植物的存活率。此外，我们还制定并应用了避免 通过使用类似于交叉配型的移植前抗体筛选来进行早期抗体介导的排斥反应 临床移植。我们进一步确定 CD4+ T 细胞是异种移植排斥的关键亚群， 在猪到灵长类肾移植模型中表现出一致的长期存活率。这些结果 代表了异种移植临床转化道路上的重大进展。在这里我们建议学习 异种移植临床转化的三大障碍：（1）所有异种移植物的长期存活 依赖于 CD40-CD154 通路的抗体阻断，目前临床上尚无 批准的试剂。我们将评估仅有的两种临床相关的 CD40-CD154 途径拮抗剂 正在开发中并已在人类患者中显示出疗效：a) Iscalimab，一种新型抗 CD40 抗体；b) VIB4920，一种创新的 CD154 靶向蛋白。这些新试剂均未经过测试 之前进行过异种移植。 (2) 我们将确定两种新型脱敏治疗的影响： 以及对早期抗体介导的排斥反应的瞬时补体抑制。我们将测试imlifidase（IdeS，一种 IgG降解酶最近被FDA批准用于预防和治疗抗体介导的疾病 排斥）以及结合共刺激阻断和蛋白酶体的创新脱敏策略 抑制。除了解决早期抗体介导的损伤之外，我们还将测试一种新的补体导向的 疗法，tesidolumab，一种抗 C5 抗体，目前正在临床试验中进行评估。我们呈现 使用新型抗 C5 抗体 tesidolumab 获得令人兴奋的数据，表明靶向补体抑制 减轻早期抗体排斥。 (3)最后我们将解决晚期抗体介导的重要问题 受伤。鉴于我们的成功，我们处于独特的地位来研究这个重要问题。与临床肾类似 移植后，我们有新的数据表明晚期肾异种移植损伤与肾移植的发展直接相关 抗 SLA II 类抗体。我们将通过删除 SLA II 类 DQ 的基因来测试这一发现的重要性 和 DR 猪供体组织并评估对排斥和保护性免疫的影响。