Evaluation of long-term toxicity of Ad/hIFN-γ, an adenoviral vector encoding the human interferon-γ gene, in nonhuman primates
Evaluation of long-term toxicity of Ad/hIFN-γ, an adenoviral vector encoding the human interferon-γ gene, in nonhuman primates
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DOI：
10.1089/hum.2007.180
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发表时间：
2008-08-01
影响因子：
4.2
通讯作者：
Huang, Wenlin
中科院分区：
文献类型：
--
作者：
Li, Yan;Shao, Jian-Yong;Huang, Wenlin
干扰素-γ（IFN-γ）在许多肿瘤细胞的免疫调节和生长抑制中发挥重要作用，但其临床应用因其全身毒性而受到限制。 Ad/hIFN-gamma 是一种编码人 IFN-gamma 的非复制腺病毒载体，据报道可在体外和异种移植模型中抑制肿瘤生长。在这项研究中，Ad/hIFN-γ 在食蟹猴（Macaca fasciculis）中的长期毒性进行了评估。将 30 只动物分为 5 组，分别肌内注射 Ad/hIFN-gamma（3.3 x 10(10)、3.3 x 10(11) 或 3.3 x 10(12) VP/kg）、Ad/LacZ（载体对照，3.3 x 10(11) VP/kg）或赋形剂，每周 3 次，持续 8 周，然后4周恢复期。 12周时，所有实验动物均表现出总体健康状况，治疗组和对照组之间的体重、尿液分析、血象、血液生化和心电图结果均无统计学显着差异。器官和组织的宏观和微观检查未发现明显的毒性作用。 Ad/IFN-γ免疫毒性的初步研究表明产生了抗腺病毒和抗hIFN-γ抗体。这些数据表明，长期、高剂量肌内注射 Ad/IFN-γ 没有明显的毒性，并且对于临床治疗用途可能是安全的。
Interferon-gamma (IFN-gamma) plays an important role in the immunomodulation and growth inhibition of many tumor cells, but its clinical application is limited by its systemic toxicity. Ad/hIFN-gamma, a nonreplicating adenoviral vector encoding human IFN-gamma, has been reported to inhibit tumor growth in vitro and in a xenograft model. In this study, the long-term toxicity of Ad/hIFN-gamma was assessed in cynomolgus macaques (Macaca fascicularis). Thirty animals were enrolled into 5 groups, and administered intramuscularly, respectively, Ad/hIFN-gamma (3.3 x 10(10), 3.3 x 10(11), or 3.3 x 10(12) VP/ kg), Ad/LacZ (vector control, 3.3 x 10(11) VP/ kg), or excipient 3 times per week for 8 weeks, followed by a 4-week recovery period. At 12 weeks all experimental animals appeared generally healthy, and there were no statistically significant differences in body weight, urinalysis, hemogram, blood biochemistry, and electrocardiogram results between the treatment and control groups. No significant toxic effects were noted on macroscopic and microscopic examinations of organs and tissues. Preliminary investigation of the immunotoxicity of Ad/IFN-gamma indicated that anti-adenoviral and anti-hIFN-gamma antibodies were generated. These data demonstrate that long-term, high-dose intramuscular administration of Ad/IFN-gamma was not notably toxic and might be safe for clinical therapeutic use.