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研究人员开发一种减少单体细胞因子剂量限制毒性的策略
2022-11-04 17:01

美国华盛顿大学David Baker,Daniel-Adriano Silva等研究人员共同合作近期取得重要工作进展,他们研究发现使用拆分后条件性激活的IL-2模拟物可减少全身性给药治疗产生的细胞因子毒性。该研究成果2022年10月31日在线发表于《自然—生物技术》杂志上。

研究人员开发了一种减少单体细胞因子剂量限制毒性的策略,方法是设计两种需要共定位才有活性的组分,它们可以独立靶向以将活性限制在同时表达两种表面标志物的细胞上。用先前设计的新白细胞介素-2/15(Neo-2/15, 白细胞介素-2和白细胞介素-15的模拟物)来演示这种方法,这两种方法都用于靶向肿瘤细胞周围的反式激活免疫细胞和顺式激活直接靶向免疫细胞。

在反式激活模式下,与全身治疗相比,肿瘤抗原靶向的两种成分增强了抗肿瘤活性,减弱了毒性。在顺式激活模式下,靶向这两种成分的免疫细胞选择性地扩增CD8T细胞,和促进嵌合抗原受体T淋巴瘤异种移植模型中的细胞活化,增强了两种情况下的抗肿瘤疗效。

据介绍,重组细胞因子的治疗潜力一直受到全身给药的严重副作用的限制。

附:英文原文

Title: A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy

Author: Quijano-Rubio, Alfredo, Bhuiyan, Aladdin M., Yang, Huilin, Leung, Isabel, Bello, Elisa, Ali, Lestat R., Zhangxu, Kevin, Perkins, Jilliane, Chun, Jung-Ho, Wang, Wentao, Lajoie, Marc J., Ravichandran, Rashmi, Kuo, Yun-Huai, Dougan, Stephanie K., Riddell, Stanley R., Spangler, Jamie B., Dougan, Michael, Silva, Daniel-Adriano, Baker, David

Issue&Volume: 2022-10-31

Abstract: The therapeutic potential of recombinant cytokines has been limited by the severe side effects of systemic administration. We describe a strategy to reduce the dose-limiting toxicities of monomeric cytokines by designing two components that require colocalization for activity and that can be independently targeted to restrict activity to cells expressing two surface markers. We demonstrate the approach with a previously designed mimetic of cytokines interleukin-2 and interleukin-15—Neoleukin-2/15 (Neo-2/15)—both for trans-activating immune cells surrounding targeted tumor cells and for cis-activating directly targeted immune cells. In trans-activation mode, tumor antigen targeting of the two components enhanced antitumor activity and attenuated toxicity compared with systemic treatment in syngeneic mouse melanoma models. In cis-activation mode, immune cell targeting of the two components selectively expanded CD8+Tcells in a syngeneic mouse melanoma model and promoted chimeric antigen receptorTcell activation in a lymphoma xenograft model, enhancing antitumor efficacy in both cases.

DOI: 10.1038/s41587-022-01510-z

Source: https://www.nature.com/articles/s41587-022-01510-z

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:68.164
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章:《自然—生物技术》:Online/在线发表

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