Selective CD28 Blockade in Renal Transplant Recipients

Belatacept是20多年来第一个被批准用于移植基石免疫抑制的新药 多年来，对移植受者有很大的好处，因为它的死亡或移植风险降低了43%。 与以钙调神经磷酸酶抑制剂为基础的方案相比，7年后丢失的方案具有显著的CNI风险- 基于肾脏毒性。然而，与对照组相比，贝拉塞特增加了急性排斥反应的风险。 他克莫司，这一事实限制了它在临床移植社区的应用，也限制了患者的使用 给它带来可观的好处。我们假设，拒绝增加背后的一个原因是 Belatacept与CD80和CD86结合，从而阻断CTLA-4介导的共抑制的配体(in 除了阻断CD28的预期效果外)。因此，在过去的7年里，我们与布里斯托尔合作- Myers Squibb将测试一种我们认为可以更好地控制同种异体反应的“下一代”CD28阻滞剂 T细胞反应和限制移植物排斥反应。在小鼠模型的临床前研究的第一阶段，我们 证明了一种新型的抗CD28结构域抗体，它特异性地结合并阻断CD28信号转导， 与CTLA-4Ig相比，保持CTLA-4共抑制不变，可以更有效地延长移植物存活时间。我们的 研究小组继续在我们的非人类灵长类前驱体内测试人类版本的抗CD28 DAb(Lulizumab)。 临床移植模型。重要的是，结果表明，抗CD28 DAb在 延长恒河猴异基因肾移植存活时间的研究。此外，lulizumab可在 皮下给药配方，消除了需要静脉输液的需要 充足的基础设施以及频繁的患者到输液中心就诊。因此，根据其预测， Lulizumab不仅疗效更好，而且更容易给药，具有变革性的潜力 移植受者的免疫抑制。考虑到其他新型试剂的匮乏， 目前，lulizumab最有希望显著改善以下免疫抑制 移植。因此，我们建议进行一项随机的第二阶段临床试验，以测试卢利珠单抗作为 与标准护理的他克莫司相比，初级免疫抑制可维持良好的肾功能， 主要终点是移植后一年的EGFR。重要的是，如果没有联邦资金 支持这项试验，lulizumab很可能永远没有机会作为免疫抑制药物进行测试 移植。因此，这项拟议的试验意义重大，因为它有可能为移植带来 一种新的免疫抑制方案，它1)比目前基于CNI的方案毒性更小，2)更多 在预防急性排斥反应方面比目前的基于贝拉泰诺的方案更有效，3)更容易和更多 方便患者就诊。结合高度细粒度和假说的临床结果高级监控 驱动机制研究将阐明人类免疫学中共信号通路的新知识，以及 有可能显著改善肾移植受者的生活质量和数量。

Belatacept, the first new agent approved for cornerstone immunosuppression in transplantation in over 20 years, offers a significant benefit to transplant recipients in that it carries a 43% reduced risk of death or graft loss after 7 years as compared to calcineurin inhibitor-based regimens which confer a significant risk of CNI- based renal toxicity. However, belatacept confers an increased risk of acute rejection as compared to tacrolimus, a fact that has limited its uptake in the clinical transplant community and limited access of patients to its considerable benefits. We hypothesized that one reason underlying this increased rejection is due to the fact that belatacept binds to CD80 and CD86, thus blocking the ligands for CTLA-4-mediated coinhibition (in addition to the intended effect of blocking CD28). As such, over the last 7 years we have partnered with Bristol- Myers Squibb to test a new “next-generation” CD28 blocker that we postulated would better control alloreactive T cell responses and limit graft rejection. In the first phase of pre-clinical investigation in a murine model, we demonstrated that a novel anti-CD28 domain antibody that specifically binds to and blocks CD28 signaling, leaving CTLA-4 coinhibition intact, more potently prolonged graft survival as compared to CTLA-4 Ig. Our team moved on to test the human version of the anti-CD28 dAb (lulizumab) in our non-human primate pre- clinical transplant model. Importantly, results reveal that the anti-CD28 dAb is superior to belatacept in prolonging allogeneic renal allograft survival in rhesus macaques. Moreover, lulizumab is available in a formulation for subcutaneous administration, eliminating the need for intravenous infusions that require sufficient infrastructure as well as frequent patient visits to an infusion center. Thus, based both on its predicted increased efficacy as well as improved ease of administration, lulizumab has the potential to be transformative immunosuppression for transplant recipients. Given the dearth of other novel reagents in the pipeline, lulizumab currently holds the most promise for significantly improving immunosuppression following transplantation. Thus, we propose a randomized, Phase II clinical trial to test the ability of lulizumab as primary immunosuppression to maintain excellent renal function vs. standard-of-care tacrolimus, with the primary endpoint being eGFR at one year post-transplant. Importantly, without federal funding to support this trial it is likely that lulizumab will never have the opportunity to be tested as immunosuppression for transplantation. Thus, the proposed trial is significant because it has the potential to bring to the transplant population a novel immunosuppressive regimen that is 1) less toxic than current CNI-based regimens, 2) more efficacious at preventing acute rejection than current belatacept-based regimens, and 3) easier and more convenient for patients. Advanced monitoring of clinical outcomes coupled with highly granular and hypothesis driven-mechanistic studies will illuminate new knowledge of cosignaling pathways in human immunology, and has the potential to significantly improve quantity and quality of life for renal transplant recipients.