Selective CD28 Blockade in Renal Transplant Recipients

贝拉西普是20多年来第一个被批准用于移植中基础免疫抑制的新药。 年，为移植受体提供了显着的好处，因为它将死亡或移植的风险降低了43 与基于钙调神经磷酸酶的方案相比，7年后的损失具有显著的CNI风险- 基于肾毒性。然而，与对照组相比，贝拉西普引起急性排斥反应的风险增加。 他克莫司，这一事实限制了其在临床移植界的应用，并限制了患者的使用 其巨大的好处。我们假设，这种增加的拒绝的一个原因是由于 事实上，贝拉西普与CD 80和CD 86结合，从而阻断了CTLA-4介导的共抑制的配体（在 除了预期的阻断CD 28的效果之外）。因此，在过去的7年里，我们与布里斯托合作- Myers Squibb测试一种新的“下一代”CD 28阻滞剂，我们假设它可以更好地控制同种异体反应性 T细胞反应和限制移植排斥。在第一阶段的临床前研究中，我们在小鼠模型中， 证明了特异性结合并阻断CD 28信号传导的新型抗CD 28结构域抗体， 与CTLA-4 IG相比，保持CTLA-4共抑制完整，更有效地延长移植物存活。我们 研究小组继续在我们的非人灵长类动物中测试抗CD 28 dAb（lulizumab）的人类版本， 临床移植模型重要的是，结果显示，抗CD 28 dAb在抗CD 28抗体方面上级贝拉西普。 延长恒河猴同种异体肾移植物的存活。此外，卢利珠单抗可以以一种 用于皮下给药的制剂，消除了需要静脉内输注的需要， 充足的基础设施以及频繁的患者访问输液中心。因此，根据其预测， 提高疗效以及改善给药的便利性，卢利珠单抗具有变革性的潜力。 对移植受者进行免疫抑制。鉴于其他新型试剂的缺乏， lulizumab目前最有希望显著改善免疫抑制， 移植因此，我们提出了一项随机化的II期临床试验，以测试鲁利珠单抗作为 与标准治疗他克莫司相比，维持良好肾功能的初级免疫抑制， 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，很可能卢利珠单抗将永远不会有机会作为免疫抑制剂进行测试， 移植因此，拟议的试验是重要的，因为它有可能带来移植， 人群一种新的免疫抑制方案，1）比目前基于CNI的方案毒性更小，2） 比目前基于贝拉西普的方案更有效地预防急性排斥反应，以及3）更容易和更有效地预防急性排斥反应。 方便患者。先进的临床结果监测，以及高度精细的假设 驱动机制研究将阐明人类免疫学中共同信号通路的新知识， 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.