Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent.
Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent.
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DOI：
10.1038/s41467-017-01385-8
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发表时间：
2017-11-09
影响因子：
16.6
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Wang P;Li X;Wang J;Gao D;Li Y;Li H;Chu Y;Zhang Z;Liu H;Jiang G;Cheng Z;Wang S;Dong J;Feng B;Chard LS;Lemoine NR;Wang Y
白细胞介素-12 （IL-12）已成为抗肿瘤免疫治疗中最有效的药物之一。然而，与全身给药IL-12相关的潜在致死毒性阻碍了其临床应用。在这里，我们重新设计了这种分子，使其抗肿瘤功效不受损害，但毒性作用被消除。IL-12的n端信号肽的缺失可以通过阻止细胞分泌IL-12来影响这种变化。我们使用一种新设计的肿瘤靶向溶瘤腺病毒（Ad-TD）向肿瘤细胞递送非分泌性（ns） IL-12，并在叙利亚仓鼠胰腺癌（PaCa）模型中检测其治疗和毒性作用。引人注目的是，与表达未修饰IL-12的Ad-TD治疗相比，腹腔注射Ad-TD- nsil -12显著提高了原位PaCa动物的存活率，并治愈了腹膜弥散性PaCa，没有毒副作用。这些发现为开发基于il -12的癌症治疗方法带来了新的希望。白细胞介素-12 （IL-12）是一种有效的免疫治疗剂。
Interleukin-12 (IL-12) has emerged as one of the most potent agents for anti-tumor immunotherapy. However, potentially lethal toxicity associated with systemic administration of IL-12 precludes its clinical application. Here we redesign the molecule in such a way that its anti-tumor efficacy is not compromised, but toxic effects are eliminated. Deletion of the N-terminal signal peptide of IL-12 can effect such a change by preventing IL-12 secretion from cells. We use a newly designed tumor-targeted oncolytic adenovirus (Ad-TD) to deliver non-secreting (ns) IL-12 to tumor cells and examine the therapeutic and toxic effects in Syrian hamster models of pancreatic cancer (PaCa). Strikingly, intraperitoneal delivery of Ad-TD-nsIL-12 significantly enhanced survival of animals with orthotopic PaCa and cured peritoneally disseminated PaCa with no toxic side effects, in contrast to the treatment with Ad-TD expressing unmodified IL-12. These findings offer renewed hope for development of IL-12-based treatments for cancer. Interleukin-12 (IL-12) is a potent immunotherapeutic agent.
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DOI：
10.1084/jem.177.4.1199
发表时间：
1993-04-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Manetti R;Parronchi P;Giudizi MG;Piccinni MP;Maggi E;Trinchieri G;Romagnani S
通讯作者：
Romagnani S
影响因子：
15.3
作者：
D'Andrea, A;Aste-Amezaga, M;Valiante, N M;Ma, X;Kubin, M;Trinchieri, G
通讯作者：
Trinchieri, G
影响因子：
5.2
作者：
Miao, Jin-Wei;Liu, Li-Jiang;Huang, Jie
通讯作者：
Huang, Jie
影响因子：
24.5
作者：
Gonzalez-Aparicio, Manuela;Alzuguren, Pilar;Hernandez-Alcoceba, Ruben
通讯作者：
Hernandez-Alcoceba, Ruben
影响因子：
15.9
作者：
Heise, C;Kirn, DH
通讯作者：
Kirn, DH