Anti-IL-10 antibody improves the therapeutic efficacy of targeted liposomal oligonucleotides
Anti-IL-10 antibody improves the therapeutic efficacy of targeted liposomal oligonucleotides
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DOI：
10.1016/j.jconrel.2009.05.006
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发表时间：
2009-09-01
影响因子：
10.8
通讯作者：
Ponzoni, Mirco
中科院分区：
文献类型：
--
作者：
Brignole, Chiara;Marimpietri, Danilo;Ponzoni, Mirco
高危神经母细胞瘤（NB）的预后仍然很差。脂质体靶向NB细胞并包封含有反义cpg的寡核苷酸（TL-asCpG），与游离asCpG相比，在NB异种移植物中具有更高的抗肿瘤效果。白细胞介素10 （IL-10）抑制抗原提呈细胞活化，促进肿瘤介导的免疫抑制。原则上，TL-asCpG与抗IL-10受体（il - 10r）抗体联合使用可以延长免疫系统的激活时间，从而获得更好的治疗效果。在人NB细胞接种后4小时，用TL-asCpG处理小鼠的存活时间明显长于对照组。在NB细胞攻击后24和72小时，接受TL-asCpG的小鼠寿命也有所延长。与仅使用TL-asCpG相比，在4小时方案中将aIL-10R加入TL-asCpG显著增加了长期幸存者的百分比。用联合策略治疗的存活小鼠完全治愈。相比之下，长期存活的小鼠只接受TL-asCpG治疗，淋巴结出现NB细胞浸润。在24小时治疗方案中，TL-asCpG联合aIL-10R治疗也明显优于TL-asCpG单独治疗。体外实验表明，与单一疗法相比，联合疗法可引起更强、更持久的免疫系统激活。这些结果支持了TL-asCpG和aIL-10R在晚期NB患者中进行临床试验的可行性。(C) 2009 Elsevier B.V.版权所有
High-risk Neuroblastoma (NB) has still a poor prognosis. Liposomes targeted to NB cells and encapsulating antisense CpG-containing oligonucleotides (TL-asCpG) had increased anti-tumour efficacy in NB xenografts compared to free asCpG. Interleukin 10 (IL-10) suppresses antigen presenting cell activation contributing to tumour-mediated immune suppression. In principle, combination of TL-asCpG and antibodies against IL-10 receptor (aIL-10R) could prolong immune system activation, leading to better therapeutic results. Mice treated with TL-asCpG 4 h after human NB cell inoculation survived significantly longer than controls. An increased life span was achieved also in mice receiving TL-asCpG 24 and 72 h after NB cell challenge. The addition of aIL-10R to TL-asCpG in the 4-h protocol significantly increased the percentage of long term survivors compared to TL-asCpG only. Surviving mice treated with the combined strategy were completely cured. In contrast, long term surviving mice treated only with TL-asCpG presented lymph node infiltration with NB cells. TL-asCpG plus aIL-10R treatment was significantly superior to TL-asCpG alone also for the 24-h protocol. Ex vivo experiments demonstrated that the combined therapy evoked a stronger and more prolonged immune system activation compared to monotherapy. These results support the feasibility of a clinical trial with TL-asCpG and aIL-10R in advanced NB patients. (C) 2009 Elsevier B.V. All rights reserved.