Humanized antibody directed to the IL-2 receptor beta-chain prolongs primate cardiac allograft survival.
Humanized antibody directed to the IL-2 receptor beta-chain prolongs primate cardiac allograft survival.
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针对 IL-2 受体 β 链的人源化抗体可延长灵长类同种异体心脏移植物的存活时间。
DOI：
10.4049/jimmunol.153.9.4330
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发表时间：
1994
影响因子：
4.4
通讯作者：
M. Tsudo
中科院分区：
文献类型：
--
作者：
S. Tinubu;J. Hakimi;J. Kondas;P. Bailon;P. Familletti;C. Spence;M. Crittenden;G. Parenteau;F. Dirbas;M. Tsudo
IL-2Rs是由外源组织相容性抗原激活的T细胞表达的，而正常细胞不表达。IL-2R表达的这种差异通过阻断IL-2RS来实现免疫抑制。高亲和力IL-2RS包括IL-2Rα、IL-2Rβ和IL-2Rγ三个亚基。小鼠Mikβ1是一种能阻断IL-2与IL-2Rβ结合的单抗，是一种免疫抑制剂。在接受小鼠Mik beta 1治疗的动物中，食蟹猴心脏移植物的存活时间略有延长(平均存活11.8±1.6天，而未治疗的动物为8.2±0.4天；p=0.06)。然而，小鼠Mikβ1在招募灵长类效应细胞方面无效，并可被针对输注的抗体的猴子抗体中和。为了绕过这些限制，开发了一种人源化形式的Mikβ1，它基本上是一种人的IgG1k抗体，只是保留了小鼠的高变区。在体内，人源化Mikβ1的血浆存活率是同时注射小鼠Mikβ1的3倍(T1/2末端，104+/-10h比37+/-2 h)。此外，人源化的Mik beta 1表现出抗体依赖的细胞毒性，这是亲代鼠Mik beta 1所缺乏的一种活性。人源化Mik beta 1治疗显著延长了移植物存活时间，存活时间分别为22、22、24、27、44和300天(p vs对照组0.01；p vs鼠Mik beta 1<；0.01)。人源化抗Tac阻断了IL-2与IL-2Rα亚基的相互作用，但并未进一步延长生存期(p>；0.3)。没有因使用Mikβ1抗体而产生的毒性。因此，人源化的Mikβ1延长了灵长类同种异体心脏移植物的存活时间，没有毒性，可能作为标准免疫抑制治疗的辅助手段有效。
IL-2Rs are expressed by T cells activated in response to foreign histocompatibility Ags but not by normal cells. This difference in IL-2R expression is exploited by blockade of IL-2Rs to achieve immunosuppression. High affinity IL-2Rs involve three subunits, IL-2R alpha, IL-2R beta, and IL-2R gamma. Murine Mik beta 1, a mAb that blocks IL-2 binding to IL-2R beta, was developed as an immunosuppressive agent. There was modest prolongation of cynomolgus cardiac allograft survival in animals treated with murine Mik beta 1 (mean survival 11.8 +/- 1.6 days compared with 8.2 +/- 0.4 days in untreated animals; p = 0.06). However, murine Mik beta 1 is ineffective in recruiting primate effector cells and is neutralized by monkey Abs directed toward the infused Ab. To circumvent these limitations, a humanized form of Mik beta 1, which is a largely human IgG1k Ab, except that murine hypervariable regions are retained, was developed. In vivo plasma survival of humanized Mik beta 1 was threefold longer than simultaneously administered murine Mik beta 1 (terminal t1/2, 104 +/- 10 h vs 37 +/- 2 h). Furthermore, humanized Mik beta 1 manifests Ab-dependent cellular cytotoxicity, an activity that is absent with the parental murine Mik beta 1. Graft survival was significantly prolonged by humanized Mik beta 1 treatment with survivals of 22, 22, 24, 27, 44, and > 300 days (p vs control < 0.01; p vs murine Mik beta 1 < 0.01). Survival was not prolonged further (p > 0.3) by the addition of humanized anti-Tac, which blocks interaction of IL-2 with IL-2R alpha subunits. There was no toxicity attributable to the use of Mik beta 1 Abs. Thus, humanized Mik beta 1 prolonged cardiac allograft survival in primates without toxicity and may be effective as an adjunct to standard immunosuppressive therapy.