Palmitate-derivatized human IL-2: a potential anticancer immunotherapeutic of low systemic toxicity

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• 作者：Sharon H. Chou (1) (2)
  Aditya V. Shetty (1) (3)
  Yajun Geng (1)
  Lipeng Xu (1) (4)
  Gnanasekar Munirathinam (1)
  Anne Pipathsouk (1)
  Isaiah Tan (1)
  Timothy Morris (1)
  Bin Wang (5)
  Aoshuang Chen (1)
  Guoxing Zheng (1)
  
• 关键词：Cancer immunotherapy ; Human IL ; 2 ; Toxicity ; Lipidation of protein ; Murine tumor models
• 刊名：Cancer Immunology, Immunotherapy
• 出版年：2013
• 出版时间：March 2013
• 年：2013
• 卷：62
• 期：3
• 页码：597-603
• 全文大小：232KB
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• 作者单位：Sharon H. Chou (1) (2)
  Aditya V. Shetty (1) (3)
  Yajun Geng (1)
  Lipeng Xu (1) (4)
  Gnanasekar Munirathinam (1)
  Anne Pipathsouk (1)
  Isaiah Tan (1)
  Timothy Morris (1)
  Bin Wang (5)
  Aoshuang Chen (1)
  Guoxing Zheng (1)
  
  1. Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, 1601 Parkview Avenue, Rockford, IL, 61107, USA
  2. Section of Adult & Pediatric Endocrinology, The University of Chicago, Chicago, IL, USA
  3. Department of Internal Medicine, University of Texas at Houston Medical School, Houston, TX, USA
  4. Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou, China
  5. Key Laboratory of Medical Molecular Virology of MOH and MOE, Fudan University, Shanghai, China
  
• ISSN：1432-0851

文摘

Purpose and experimental design Recombinant human IL-2 (rhIL-2) is a potent cytokine and FDA-approved anticancer drug. However, its clinical use has been limited by severe toxicity, associated primarily with systemic administration with excess protein distributing freely throughout the body. We hypothesized that rhIL-2 in alternate forms permitting more restricted localization may exert stronger antitumor efficacy and less toxicity. Here, we have tested the utility of palmitate-derivatized rhIL-2. rhIL-2 was reacted with N-hydroxysuccinimide palmitate ester. The resultant lipidated rhIL-2 (pIL-2), when mixed with cells, could spontaneously transfer from solution to cell surfaces. Next, anticancer efficacy of pIL-2 was assessed in two modalities. For adoptive T cell therapy, antitumor cytotoxic T cells (CTLs) were protein transferred (“painted- with pIL-2 and injected into mice bearing lymphoma. For in situ therapy, pIL-2 was injected intratumorally into mice bearing melanoma. Tumor growth and IL-2-associated toxicity were determined. Results In the lymphoma model, painting of the antitumor CTLs with pIL-2 markedly increased their viability and titer. In the melanoma model, intratumoral injection of pIL-2, but not rhIL-2, increased the number of activated CD8+ T cells (IFN-γ+) in the spleen, reduced lung metastasis and prolonged the survival of treated mice. Moreover, while repeated intratumoral injection of rhIL-2 at an excessively high dose (10 injections of 10,000?IU/mouse) caused marked vascular leakage syndrome, the same regimen using pIL-2 caused no detectable toxicity. Conclusions Transferring spontaneously from solution to cell surfaces, pIL-2 may bypass the current limitations of rhIL-2 and, thus, serve as a more effective and tolerable anticancer drug.