Comparative in vitro study of the immunomodulatory activity of humanized and chimeric anti-CD25 monoclonal antibodies
Comparative in vitro study of the immunomodulatory activity of humanized and chimeric anti-CD25 monoclonal antibodies
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DOI：
10.1111/j.1365-2249.2003.02324.x
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发表时间：
2003-12-01
影响因子：
4.6
通讯作者：
Nachbaur, D
中科院分区：
文献类型：
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作者：
Kircher, B;Lätzer, K;Nachbaur, D
针对白细胞介素-2 （IL-2）受体α链CD25的人源化或嵌合单克隆抗体（MoAbs）由于其改善的药代动力学特征和较低的毒性，是很有前途的免疫抑制剂。这些MoAbs已被有效地用于预防和/或治疗实体器官移植中的排斥反应，目前正在研究用于预防/治疗干细胞移植中的移植物抗宿主病（GvHD）。我们分析了嵌合抗cd25 MoAb basiliximab和人源化抗cd25 MoAb daclizumab在不同测试系统中的同种免疫反应和T细胞活化活性，并与环孢素A （CsA）和强的松龙进行了比较。抗cd25 MoAbs可显著降低抗cd3和同种异体抗原诱导的T细胞增殖，并呈剂量依赖性。当浓度为10 ng/ml时，daclizumab和CsA协同降低混合淋巴细胞培养的T细胞增殖，而basiliximab仅显示亚加性活性。同时加入抗cd25 MoAbs和强的松龙不会产生联合活性。外源IL-2的加入完全克服了抗cd25 MoAbs对T细胞增殖的抑制作用，但CsA和泼尼松龙却不能。在限制性稀释试验中，抗cd25 MoAbs抑制抗原特异性细胞毒性T淋巴细胞的产生，而它们对已建立的抗原特异性T细胞克隆的细胞溶解活性没有影响。这项体外研究表明嵌合和人源化moab抗体对CD25具有很强的免疫抑制活性。与CsA的联合活性证明它们早期用于预防而不是治疗GvHD是合理的。
Humanized or chimeric monoclonal antibodies (MoAbs) directed against the interleukin-2 (IL-2) receptor alpha-chain, CD25, are promising immunosuppressive agents due to improved pharmacokinetic profiles and less toxicity. These MoAbs have been used effectively in preventing and/or treating rejection in solid organ transplantation and are currently under investigation for prevention/treatment of graft-versus-host disease (GvHD) in stem cell transplantation. We analysed the in vitro activities of the chimeric anti-CD25 MoAb basiliximab and the humanized anti-CD25 MoAb daclizumab in various test systems for alloimmune response and T cell activation in comparison to cyclosporin A (CsA) and prednisolone. Anti-CD3- and alloantigen-induced T cell proliferation were decreased significantly by the anti-CD25 MoAbs in a dose-dependent fashion. At a concentration of 10 ng/ml daclizumab and CsA synergistically decreased T cell proliferation of mixed lymphocyte cultures, whereas basiliximab showed only subadditive activity. Simultaneous addition of the anti-CD25 MoAbs and prednisolone did not result in combined activity. Addition of exogenous IL-2 completely overcame the inhibitory effect on T cell proliferation of both anti-CD25 MoAbs, but not that of CsA and prednisolone. Anti-CD25 MoAbs inhibited the generation of antigen-specific cytotoxic T lymphocytes in a limiting dilution assay, whereas they showed no effect on the cytolytic activity of established antigen-specific T cell clones. This in vitro study demonstrates strong immunosuppressive activity by both chimeric and humanized MoAbs against CD25. The combined activity with CsA justifies their early use for prevention rather than treatment of GvHD.