Strategies to Optimize Pig-to Primate Kidney Xenograft Survival

现在有超过10万名患者在等待肾脏移植，很明显， 缺乏可用的捐赠器官。异种移植是一种很有前途的解决办法。猪是 作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 阻碍了猪到人的肾移植的临床应用。在本申请中，我们提出 使用尖端的基因工程方法结合新的，临床相关的免疫， 抑制剂，以减少非人灵长类动物的体液和细胞免疫反应， 异种肾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， 基因组编辑技术，我们和其他人创造了具有多种遗传改变的新型猪供体， 从而提高异种移植物的存活率。此外，我们还制定并实施了避免 早期抗体介导的排斥反应，通过使用类似于交叉配型的移植前抗体筛选， 临床移植我们进一步鉴定了CD 4 + T细胞作为异种移植排斥反应的关键亚群， 在猪-灵长类动物肾移植模型中表现出一致的长期存活。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，我们建议研究 异种移植临床转化的三个主要障碍：（1）所有长期异种移植物存活都有 依赖于CD 40-CD 154通路的抗体阻断，目前临床上没有 批准的试剂。我们将评估仅有的两种临床相关的CD 40-CD 154通路拮抗剂， 在开发中并已在人类患者中显示功效：a）Iscalimab，一种新型抗-CD 40抗体，和B） VIB 4920，一种创新的CD 154靶向蛋白。这两种新试剂都没有在 异种移植手术前(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。我们将测试伊立非达酶（IdeS， IgG降解酶最近被FDA批准用于预防和治疗抗体介导的 排斥）以及结合共刺激阻断和蛋白酶体的创新脱敏策略 抑制作用除了解决早期抗体介导的损伤，我们将测试一种新的补体介导的损伤。 治疗，特斯多鲁单抗，目前正在临床试验中评估的抗C5抗体。我们提出 使用新型抗C5抗体特斯多鲁单抗的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，我们将讨论晚期抗体介导的重要问题。 损伤鉴于我们的成功，我们处于研究这一重要问题的独特地位。与临床肾脏相似 移植后，我们有新的数据表明，晚期异种肾移植损伤与移植后肾功能的发展直接相关。 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在猪供体组织中的表达，并评估对排斥反应和保护性免疫的影响。

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.