Strategies to Optimize Pig-to Primate Kidney Xenograft Survival

目前有超过10万名患者在等待肾脏移植，显然有一个关键的 可供捐献的器官短缺。异种移植是一种很有前途的解决方案。而猪则是 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 阻碍了猪对人肾移植的临床应用。在本申请中，我们建议 使用尖端基因工程方法与新颖的、临床相关的免疫- 抑制药物降低非人类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。随着最近在以下方面的进展 基因组编辑技术我们和其他人创造了具有多种基因改变和 随之而来的异种移植物存活率的改善。此外，我们还制定和应用了战略，以避免 移植前抗体筛查类似于交叉配型的早期抗体介导的排斥反应 临床移植。我们进一步确定了CD4+T细胞是异种移植排斥反应的关键亚群 在猪到灵长类动物的肾脏移植模型中显示出一致的长期存活。这些结果 在异种移植临床移植的道路上取得了重大进展。在这里，我们建议研究 异种移植临床移植的三大障碍：(1)所有长期存活的异种移植 依赖于抗体对CD40-CD154通路的阻断，目前还没有临床应用 认可试剂。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)一种新的抗CD40抗体Iscalimab和b) VIB4920，一种创新的CD154靶向蛋白。这两种新试剂都没有在 以前的异种移植。(2)我们将确定两种新型脱敏疗法的影响，包括 以及对抗体介导的早期排斥反应的短暂补体抑制。我们将测试imlifidase(IDES，AND 免疫球蛋白降解酶最近被FDA批准用于预防和治疗抗体介导的疾病 排斥)以及结合了共刺激、阻断和蛋白酶体的创新脱敏策略 抑制力。除了解决早期抗体介导的损伤外，我们还将测试一种新的补体导向的损伤 治疗，tesidolumab，一种抗C5抗体，目前正在临床试验中进行评估。我们呈现的是 使用新型抗C5抗体tesidolumab的令人兴奋的数据表明，靶向抑制补体 减轻早期抗体排斥反应。(3)最后，我们将讨论晚期抗体介导的重要问题 受伤。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，我们有新的数据表明，晚期异种肾移植的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在猪供体组织中的表达，并评估其对排斥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.