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The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors.
以抗体为基础的 interleukin-12 递送至实体肿瘤可增强 NK 和 CD8 + T 细胞活性,并与免疫检查点抑制剂协同作用。
EDB domain of fibronectin antibody-cytokine fusions immune checkpoint blockade immunotherapy interleukin-12
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摘要

We describe the cloning and characterization of a novel fusion protein (termed L19-mIL12), consisting of murine interleukin-12 in single-chain format, sequentially fused to the L19 antibody in tandem diabody format. The fusion protein bound avidly to the cognate antigen (the alternatively spliced EDB domain of fibronectin), retained the activity of the parental cytokine and was able to selectively localize to murine tumors in vivo, as shown by quantitative biodistribution analysis. L19-mIL12 exhibited a potent antitumor activity in immunocompetent mice bearing CT26 carcinomas and WEHI-164 sarcomas, which could be boosted by combination with checkpoint blockade, leading to durable cancer eradication. L19-mIL12 also inhibited tumor growth in mice with Lewis lung carcinoma (LLC), but in this case, cancer cures could not be obtained, both in monotherapy and in combination. A microscopic analysis and a depletion experiment of tumor-infiltrating leukocytes illustrated the contribution of NK cells and CD8+ T cells for the anticancer activity observed in both tumor models. Upon L19-mIL12 treatment, the density of regulatory T cells (Tregs) was strongly increased in LLC, but not in CT26 tumors. A FACS analysis also revealed that the majority of CD8+ T cells in CT26 tumors were specific to the retroviral AH1 antigen.

译文

我们描述了一种新的融合蛋白 (称为 L19-mIL12) 的克隆和表征,该蛋白由单链形式的小鼠 interleukin-12 组成,以串联 diabody 形式连续融合到 L19 抗体。融合蛋白热切地与同源抗原结合 (纤维连接蛋白的选择性剪接 EDB 结构域),保留亲代细胞因子的活性,并能够选择性地定位到体内的小鼠肿瘤, 如定量生物分布分析所示。L19-mIL12 在携带 CT26 癌和 WEHI-164 肉瘤的免疫活性小鼠中表现出强有力的抗肿瘤活性,这可以通过结合检查点阻断来提高,从而持久根除癌症。L19-mIL12 还抑制了 Lewis 肺癌 (LLC) 小鼠的肿瘤生长,但在这种情况下,无论是单一疗法还是联合疗法都无法获得癌症治疗。肿瘤浸润白细胞的微观分析和耗竭实验说明了 NK 细胞和 CD8 T 细胞对在两种肿瘤模型中观察到的抗癌活性的贡献。在 L19-mIL12 治疗后,LLC 中调节性 T 细胞 (Tregs) 的密度显著增加,但 CT26 肿瘤中没有。FACS 分析还显示,CT26 肿瘤中的大多数 CD8 T 细胞对逆转录病毒 AH1 抗原具有特异性。

Interleukin 12

肿瘤 白细胞介素 临床研究术语
概述  :  

白细胞介素12属于Th1型细胞因子,是白介素家族近年来发现的新成员,是联接非特异性先天免疫与抗原特异适应性免疫的关键分子,在介导机体对抗原的免疫排斥过程中起重要作用。它是异源二聚体细胞因子,分子量为70 KD(P70),由分子量分别为40 KD(P40)与35 KD(P35)的两条糖基链经二硫链连接组成。是已知对细胞免疫活性诱导和调节作用最强的多功能细胞因子,其作为沟通非特异性先天免疫和抗原特异适应性免疫的桥梁,参与感染、肿瘤、自体免疫等疾病的发病过程。IL-1

Interleukin   英 /ɪn'tə'lʊkɪn/   美 /ɪn'tə'lʊkɪn/

释    义   n. [生化] 白介素

例    句   This study was designed to investigate the treatment of spontaneous metastatic lung cancer by interleukin 12 ( IL 12) gene modified dendritic cells (DC) vaccine. 本研究目的是探讨白介素12(IL-12)基因修饰的树突细胞(DC)疫苗对自发性转移性肺癌的治疗作用。

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