Effects of combining anti-CD40 and anti-CD11b mAb107 on survival of pig kidney xenografts in cynomolgus monkeys

项目摘要/摘要 使用基于CD154的抗CD154方案阻断CD40-CD154共刺激通路已有显著改善 基因编辑的猪器官异种移植在非人灵长类动物(NHP)受体中的存活。然而，危及生命的 与使用抗CD154相关的血栓栓塞并发症使其不能被批准用于人类。 试图通过阻断CD40来避免这种并发症，CD40是经典的CD154受体，自相矛盾地阻碍了 促进了NHP受者的耐受诱导。最近的一项研究表明，阻断第二个CD154 整合素CD11b受体显著增加了抗CD40在延长小鼠同种异体移植物存活方面的效果。 尽管鼠标模型对于开发概念验证很重要，但如果组合在一起仍有待确定 研究表明，阻断CD40和CD11b可以延长NHP接受者的异种移植存活时间 将是指导临床翻译的关键。在初步研究中，我们发现一种抗CD11b单抗具有独特的 作用机制不仅可阻止多配体与CD11b结合，还可阻断直接和间接NHP T细胞 NHP受者移植肾的同种异体反应和延长存活时间。这次探索性的主要目的是 R21是为了检验这样的假设，即将这种单抗与抗CD40结合更安全，相当于甚至更多 在我们建立的基因编辑猪到NHP中，比抗CD154抗体更有效地延长了异种肾移植的存活时间 异种移植模型。这项研究的第二个目标是评估这种联合封锁对 非霍奇金淋巴瘤治疗后T细胞亚群的计数及功能如果成功，这些研究可能会为 延长异种移植肾存活时间，从而解决了一个迫切但尚未得到满足的医疗需求。

Project Summary/Abstract Disrupting the CD40-CD154 costimulatory pathway using an anti-CD154-based regimen has markedly improved gene-edited pig organ xenograft survival in nonhuman primate (NHP) recipients. However, the life-threatening thromboembolic complications associated with use of anti-CD154 have precluded its approval for human use. Attempts to avoid this complication by blocking CD40, the classic CD154 receptor, paradoxically impeded rather than promoted tolerance induction in NHP recipients. A recent study showed that blocking a second CD154 receptor, integrin CD11b, significantly increased efficacy of anti-CD40 in prolonging allograft survival in mice. Although mouse models are important for developing proof-of-concept, it remains to be determined if combined blockade of CD40 and CD11b can be extended to prolonging survival of xenografts in NHP recipients, studies that will be critical for guiding clinical translation. In preliminary studies, we show that an anti-CD11b mAb with a unique mechanism of action not only prevents multiligand binding to CD11b but also blocks direct and indirect NHP T cell alloresponses and prolongs survival of kidney allografts in NHP recipients. The main objective of this exploratory R21 is to test the hypothesis that combining this mAb with anti-CD40 is safer and equivalent to or even more effective than anti-CD154 in prolonging kidney xenograft survival in our established gene-edited pig-to-NHP xenotransplantation model. A second objective of this study is to evaluate the effect of this combined blockade on enumeration and function of T cell subsets in treated NHP. If successful, these studies may provide a basis for prolonging kidney xenograft survival, thus addressing a pressing yet unmet medical need.