Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent
Pengju Wang, Xiaozhu Li, Jiwei Wang, Dongling Gao, Yuenan Li, Haoze Li, Yongchao Chu, Zhongxian Zhang, Hongtao Liu, Guozhong Jiang, Zhenguo Cheng, Shengdian Wang, Jianzeng Dong, Baisui Feng, Louisa S Chard, Nicholas R Lemoine, Yaohe Wang, Pengju Wang, Xiaozhu Li, Jiwei Wang, Dongling Gao, Yuenan Li, Haoze Li, Yongchao Chu, Zhongxian Zhang, Hongtao Liu, Guozhong Jiang, Zhenguo Cheng, Shengdian Wang, Jianzeng Dong, Baisui Feng, Louisa S Chard, Nicholas R Lemoine, Yaohe Wang
Abstract
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.
Conflict of interest statement
Y.W., P.W., D.G., and N.R.L. are inventors of a filed patent application relevant to this study. The remaining authors declare no competing financial interests.
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References
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