Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker
Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker
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DOI：
10.1038/s41551-022-00888-0
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发表时间：
2022-05-09
影响因子：
28.1
通讯作者：
Hubbell, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Mansurov, Aslan;Hosseinchi, Peyman;Hubbell, Jeffrey A.
通过可被肿瘤相关蛋白酶裂解的连接体，用白细胞介素 12 受体的结构域掩蔽白细胞介素 12，可消除全身免疫相关的不良事件，并在携带免疫冷肿瘤的小鼠中引发有效的治疗效果。免疫检查点抑制剂已显示出针对免疫“冷”肿瘤的适度功效。白细胞介素-12 (IL-12) 是一种细胞因子，可促进免疫细胞募集至肿瘤以及免疫细胞激活，在冷肿瘤中也是如此，可导致患者出现严重的免疫相关不良事件。在这里，通过利用肿瘤中蛋白酶的优先过度表达，我们表明，通过肿瘤相关蛋白酶可裂解的接头将 IL-12 受体的结构域与 IL-12 融合，很大程度上限制了 IL-12 对肿瘤部位的促炎作用。在皮下腺癌和原位黑色素瘤的小鼠模型中，静脉注射的掩蔽IL-12不会引起全身性IL-12信号传导，并消除了全身性免疫相关不良事件，通过重塑免疫抑制微环境产生有效的治疗效果，并使冷肿瘤对免疫检查点抑制产生反应。我们还表明，掩蔽的 IL-12 在患者的肿瘤裂解物中被激活。蛋白酶敏感的强效但有毒的细胞因子掩蔽可能有助于其临床转化。
Masking interleukin-12 with a domain of the interleukin-12 receptor via a linker cleavable by tumour-associated proteases eliminates systemic immune-related adverse events and triggers potent therapeutic effects in mice bearing immunologically cold tumours.Immune-checkpoint inhibitors have shown modest efficacy against immunologically 'cold' tumours. Interleukin-12 (IL-12)-a cytokine that promotes the recruitment of immune cells into tumours as well as immune cell activation, also in cold tumours-can cause severe immune-related adverse events in patients. Here, by exploiting the preferential overexpression of proteases in tumours, we show that fusing a domain of the IL-12 receptor to IL-12 via a linker cleavable by tumour-associated proteases largely restricts the pro-inflammatory effects of IL-12 to tumour sites. In mouse models of subcutaneous adenocarcinoma and orthotopic melanoma, masked IL-12 delivered intravenously did not cause systemic IL-12 signalling and eliminated systemic immune-related adverse events, led to potent therapeutic effects via the remodelling of the immune-suppressive microenvironment, and rendered cold tumours responsive to immune-checkpoint inhibition. We also show that masked IL-12 is activated in tumour lysates from patients. Protease-sensitive masking of potent yet toxic cytokines may facilitate their clinical translation.