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名患者在肾脏移植的候补名单上，很明显，有一个关键 缺乏可用的供体器官。异种移植代表了一个有前途的解决方案。猪是 被视为最佳的非人类器官来源，人类免疫反应对猪器官的效力 已经阻止了猪到人类肾脏移植的临床应用。在此应用程序中，我们建议 使用尖端的基因工程方法与新型的临床相关免疫 - 抑制剂以减少非人类灵长类动物的体液和细胞免疫反应 肾脏异种移植作为临床前模型，以告知未来的人类试验。随着最近的进步 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， 异种移植存活的结果改善。此外，我们已经制定并采用了策略来避免 通过使用前移植抗体筛查类似于使用的交叉抗体筛选，早期抗体介导的排斥反应 临床移植。我们进一步将CD4+ T细胞确定为异种移植排斥反应中的关键子集和 在猪到顶峰的肾脏移植模型中表现出一致的长期生存。这些结果 代表了异种移植临床翻译道路的重大进步。在这里我们建议学习 异种移植临床翻译的三个主要障碍：（1）所有长期异种移植存活率均具有 依赖于CD40-CD154途径的抗体阻断，目前尚无临床 批准的试剂。我们将评估仅有的两个临床相关的CD40-CD154途径拮抗剂 在发育中并显示了人类患者的功效：a）iScalimab，一种新型抗CD40抗体和B） VIB4920，一种创新的CD154靶向蛋白。这些新试剂均未在 异种移植以前。 （2）我们将确定两种新型脱敏处理的影响 以及对早期抗体介导的排斥反应的瞬时补体抑制作用。我们将测试Imlifidase（ides，一个 IgG降解酶最近被FDA批准用于预防和治疗抗体介导的 拒绝）以及结合共刺激封锁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，我们还将测试新的补体指导 治疗，Tesidolumab，一种抗C5抗体，目前正在临床试验中进行评估。我们在场 使用新型抗C5抗体Tesidolumab的令人兴奋的数据，表明靶向补体抑制作用 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，我们可以独特地研究这个重要问题。类似于临床肾脏 移植，我们有新的数据，即晚期肾脏异种移植损伤与发展直接相关 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 和猪供体组织中的DR并评估对排斥和保护性免疫的影响。