Nondepleting anti-CD40-based therapy prolongs allograft survival in nonhuman primates.
Nondepleting anti-CD40-based therapy prolongs allograft survival in nonhuman primates.
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DOI：
10.1111/j.1600-6143.2011.03736.x
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Larsen CP
中科院分区：
文献类型：
--
作者：
Badell IR;Thompson PW;Turner AP;Russell MC;Avila JG;Cano JA;Robertson JM;Leopardi FV;Strobert EA;Iwakoshi NN;Reimann KA;Ford ML;Kirk AD;Larsen CP
在许多移植模型中，共刺激阻断CD40/CD154通路在预防同种异体移植排斥反应方面是有效的。这一策略在很大程度上依赖于针对CD154的单抗，由于其与血栓栓子事件的关联，限制了翻译的可能性。尽管靶向CD40作为CD154的替代品已经在临床前模型中成功地预防了同种异体移植排斥反应，但还没有关于CD40特异性药物在人类移植受者中的作用的报道。这种临床翻译的延迟可能部分是由于存在许多CD40特异性单抗的细胞耗竭。因此，CD40导向免疫治疗的最佳生物学特性仍有待确定。在这份报告中，我们鉴定了3A8，一种人类CD40特异性单抗，并在恒河猴胰岛细胞移植模型中评估了它的疗效。尽管3A8具有部分激动性，且在体外不能阻断CD40与可溶性CD154(SCD154)的结合，但基于3A8的治疗显著延长了同种异体胰岛移植物的存活时间，而不会耗尽B细胞。我们的结果表明，CD40导向的共刺激阻断的同种异体移植物保护作用不需要sCD154阻断、完全拮抗或细胞耗竭，并有助于支持和指导CD40特异性药物的继续开发用于临床翻译。
Costimulation blockade of the CD40/CD154 pathway has been effective at preventing allograft rejection in numerous transplantation models. This strategy has largely depended on mAbs directed against CD154, limiting the potential for translation due to its association with thromboembolic events. Though targeting CD40 as an alternative to CD154 has been successful at preventing allograft rejection in preclinical models, there have been no reports on the effects of CD40-specific agents in human transplant recipients. This delay in clinical translation may in part be explained by the presence of cellular depletion with many CD40-specific mAbs. As such, the optimal biologic properties of CD40-directed immunotherapy remain to be determined. In this report, we have characterized 3A8, a human CD40-specific mAb and evaluated its efficacy in a rhesus macaque model of islet cell transplantation. Despite partially agonistic properties and the inability to block CD40 binding of soluble CD154 (sCD154) in vitro, 3A8-based therapy markedly prolonged islet allograft survival without depleting B cells. Our results indicate that the allograft-protective effects of CD40-directed costimulation blockade do not require sCD154 blockade, complete antagonism or cellular depletion, and serve to support and guide the continued development of CD40-specific agents for clinical translation.
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