Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin.
Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin.
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DOI：
10.1016/j.molonc.2015.11.008
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发表时间：
2016-04
影响因子：
6.6
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Wang Z;Pratts SG;Zhang H;Spencer PJ;Yu R;Tonsho M;Shah JA;Tanabe T;Powell HR;Huang CA;Madsen JC;Sachs DH;Wang Z
调节性T细胞（Regulatory T cells，Treg）在调节免疫应答中起着重要作用，在肿瘤治疗、移植和自身免疫性疾病等领域受到越来越多的关注。CC趋化因子受体4（CCR 4）在大多数TcB上表达，尤其是在效应TcB上。最近，我们已经开发了一种基于白喉毒素的抗人CCR 4免疫毒素，用于体内消耗CCR 4+细胞。在这项研究中，我们证明了抗人CCR 4免疫毒素在体外结合和耗尽猴CCR 4+细胞。我们还证明了免疫毒素在体外与CCR 4 + Foxp 3+猴TCR 4结合。在两只未经处理的食蟹猴中进行的体内研究显示，外周血中78-89%的CCR 4 + Foxp 3 + Treg消耗持续约10天。在淋巴结中，89-96%的CCR 4 + Foxp 3 + T细胞被耗尽。在其他细胞群中未观察到影响，包括CD 8 + T细胞、其他CD 4 + T细胞、B细胞和NK细胞。据我们所知，这是第一种有效耗尽非人灵长类动物（NHP）THP的药物。这种免疫毒素具有耗尽效应物Tcl 3用于联合癌症治疗的潜力。
Regulatory T cells (Treg) play an important role in modulating the immune response and has attracted increasing attention in diverse fields such as cancer treatment, transplantation and autoimmune diseases. CC chemokine receptor 4 (CCR4) is expressed on the majority of Tregs, especially on effector Tregs. Recently we have developed a diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4+ cells in vivo. In this study, we demonstrated that the anti-human CCR4 immunotoxin bound and depleted monkey CCR4+ cells in vitro. We also demonstrated that the immunotoxin bound to the CCR4+Foxp3+ monkey Tregs in vitro. In vivo studies performed in two naive cynomolgus monkeys revealed 78–89% CCR4+Foxp3+ Treg depletion in peripheral blood lasting approximately 10 days. In lymph nodes, 89–96% CCR4+Foxp3+ Tregs were depleted. No effect was observed in other cell populations including CD8+ T cells, other CD4+ T cells, B cells and NK cells. To our knowledge, this is the first agent that effectively depleted non-human primate (NHP) Tregs. This immunotoxin has potential to deplete effector Tregs for combined cancer treatment.