Tinubu S A, Hakimi J, Kondas J A, Bailon P, Familletti P C, Spence C, Crittenden M D, Parenteau G L, Dirbas F M, Tsudo M
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1994 Nov 1;153(9):4330-8.
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.
IL-2受体由对外来组织相容性抗原作出反应而被激活的T细胞表达，正常细胞则不表达。IL-2受体表达的这种差异被用于通过阻断IL-2受体来实现免疫抑制。高亲和力IL-2受体由三个亚基组成，即IL-2Rα、IL-2Rβ和IL-2Rγ。鼠源Mikβ1是一种阻断IL-2与IL-2Rβ结合的单克隆抗体，被开发用作免疫抑制剂。在用鼠源Mikβ1治疗的动物中，食蟹猴心脏同种异体移植的存活时间有适度延长（平均存活时间为11.8±1.6天，未治疗动物为8.2±0.4天；p = 0.06）。然而，鼠源Mikβ1在募集灵长类效应细胞方面无效，并且会被针对注入抗体的猴抗体中和。为了克服这些局限性，开发了一种人源化形式的Mikβ1，它基本上是一种人IgG1k抗体，只是保留了鼠源高变区。人源化Mikβ1在体内的血浆存活时间比同时给予的鼠源Mikβ1长三倍（终末t1/2，104±10小时对37±2小时）。此外，人源化Mikβ1表现出抗体依赖性细胞毒性，而亲本鼠源Mikβ1则没有这种活性。人源化Mikβ1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（与对照组相比p<0.01；与鼠源Mikβ1相比p<0.01）。加入阻断IL-2与IL-2Rα亚基相互作用的人源化抗Tac后，存活时间没有进一步延长（p>0.3）。使用Mikβ1抗体没有毒性。因此，人源化Mikβ1延长了灵长类动物心脏同种异体移植的存活时间且无毒性，可能作为标准免疫抑制治疗的辅助药物有效。
