Background

Post-transplant ischemia reperfusion injury (IRI) is a recognized risk factor for subsequent organ dysfunction, alloresponsiveness, and rejection. The complement system is known to play a role in IRI and represents a therapeutic target. Complement is activated in transplanted grafts when circulating IgM antibodies bind to exposed ischemia-induced neoepitopes upon reperfusion, and we investigated the targeting of a human complement inhibitor, CR1, to a post-transplant ischemia-induced neoepitope.

Methods

A fragment of human CR1 was linked to a single chain antibody construct (C2 scFv) recognizing an injury-specific neoepitope to yield C2-CR1. This construct, along with a soluble untargeted counterpart, was characterized in a cardiac allograft transplantation model of IRI in terms of efficacy and safety.

Results

CR1 was similarly effective against mouse and human complement. C2-CR1 provided effective protection against cardiac IRI at a lower dose than untargeted CR1. The increased efficacy of C2-CR1 relative to CR1 correlated with decreased C3 deposition, and C2-CR1, but not CR1, targeted to cardiac allografts. At a dose necessary to reduce IRI, C2-CR1 had minimal impact on serum complement activity, in contrast to CR1 which resulted in a high level of systemic inhibition. The circulatory half-life of CR1 was markedly longer than that of C2-CR1, and whereas a minimum therapeutic dose of CR1 severely impaired host susceptibility to infection, C2-CR1 had no impact.

Conclusion

We show the translational potential of a human complement inhibitor targeted to a universal ischemia-induced graft-specific epitope, and demonstrate advantages compared to an untargeted counterpart in terms of efficacy and safety.

中文翻译：

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通过靶向移植物特异性新表位，提高人类补体抑制剂治疗移植后心脏缺血再灌注损伤的功效和安全性

 背景

移植后缺血再灌注损伤（IRI）是随后器官功能障碍、同种异体反应性和排斥反应的公认危险因素。已知补体系统在 IRI 中发挥作用并代表治疗靶点。当循环 IgM 抗体与再灌注时暴露的缺血诱导的新表位结合时，移植移植物中的补体被激活，我们研究了人补体抑制剂 CR1 靶向移植后缺血诱导的新表位。

 方法

将人 CR1 的片段与识别损伤特异性新表位的单链抗体构建体 (C2 scFv) 连接，产生 C2-CR1。该构建体以及可溶性非靶向对应物在 IRI 心脏同种异体移植模型中的有效性和安全性进行了表征。

 结果

CR1 对小鼠和人类补体也同样有效。 C2-CR1 以低于非靶向 CR1 的剂量提供了针对心脏 IRI 的有效保护。 C2-CR1 相对于 CR1 的功效增强与 C3 沉积减少相关，并且 C2-CR1（而非 CR1）靶向心脏同种异体移植物。在降低 IRI 所需的剂量下，C2-CR1 对血清补体活性的影响最小，而 CR1 则导致高水平的全身抑制。 CR1的循环半衰期明显长于C2-CR1，尽管CR1的最小治疗剂量会严重损害宿主对感染的易感性，但C2-CR1却没有影响。

 结论

我们展示了针对通用缺血诱导的移植物特异性表位的人类补体抑制剂的转化潜力，并证明了与非靶向对应物相比在功效和安全性方面的优势。