Increasing the efficacy and safety of a human complement inhibitor for treating post-transplant cardiac ischemia reperfusion injury by targeting to a graft-specific neoepitope.
Increasing the efficacy and safety of a human complement inhibitor for treating post-transplant cardiac ischemia reperfusion injury by targeting to a graft-specific neoepitope.
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DOI：
10.1016/j.healun.2021.07.004
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发表时间：
2021-10
影响因子：
8.9
通讯作者：
Tomlinson, Stephen
中科院分区：
文献类型：
--
作者：
Zheng, Chaowen;Sleiman, Mohamad Mahdi;Yang, Xiaofeng;He, Songqing;Atkinson, Carl;Tomlinson, Stephen
Post-transplant ischemia reperfusion injury (IRI) is a recognized risk factor for subsequent organ dysfunction, alloresponsiveness, and rejection. Complement 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. 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. 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. 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.
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DOI：
10.4049/jimmunol.1102132
发表时间：
2012-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Elvington A;Atkinson C;Kulik L;Zhu H;Yu J;Kindy MS;Holers VM;Tomlinson S
通讯作者：
Tomlinson S
影响因子：
4.4
作者：
Tuck MK;Chan DW;Chia D;Godwin AK;Grizzle WE;Krueger KE;Rom W;Sanda M;Sorbara L;Stass S;Wang W;Brenner DE
通讯作者：
Brenner DE
DOI：
10.1002/hep.29512
发表时间：
2018-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Marshall K;Jin J;Atkinson C;Alawieh A;Qiao F;Lei B;Chavin KD;He S;Tomlinson S
通讯作者：
Tomlinson S
DOI：
10.4049/jimmunol.0803980
发表时间：
2009-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kulik L;Fleming SD;Moratz C;Reuter JW;Novikov A;Chen K;Andrews KA;Markaryan A;Quigg RJ;Silverman GJ;Tsokos GC;Holers VM
通讯作者：
Holers VM
靶向补体抑制剂可预防移植后心脏缺血和再灌注损伤，并揭示补体激活替代途径的重要作用
影响因子：
4.4
作者：
Atkinson, Carl;He, Songqing;Tomlinson, Stephen
通讯作者：
Tomlinson, Stephen