Targeting IFN-α to B cell lymphoma by a tumor-specific antibody elicits potent antitumor activities
Targeting IFN-α to B cell lymphoma by a tumor-specific antibody elicits potent antitumor activities
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DOI：
10.4049/jimmunol.179.10.6881
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发表时间：
2007-11-15
影响因子：
4.4
通讯作者：
Morrison, Sherie L.
中科院分区：
文献类型：
--
作者：
Huang, Tzu-Hsuan;Chintalacharuvu, Koteswara R.;Morrison, Sherie L.
IFN-α是一种对先天免疫应答至关重要的细胞因子，也显示出抗肿瘤活性。然而，IFN-α作为抗癌药物的使用受到其短半衰期和毒性的阻碍。改善IFN-α治疗指数的一种方法是通过将其融合到肿瘤特异性Ab来增加其半衰期和肿瘤定位。在本研究中，我们构建了由抗HER2/neu-IgG3和IFN-α组成的融合蛋白（抗HER2/neu-IgG3-IFN-α），并研究了其对表达人HER2/neu的小鼠B细胞淋巴瘤38 C13的作用。抗HER2/neu-IgG3-IFN-α在体内表现出对38 C13/HER2肿瘤生长的强效抑制。在肿瘤攻击后1天开始，每天给予3次1 μ g剂量的抗HER2/neu-IgG3-IFN-α，导致88%的小鼠保持无肿瘤。值得注意的是，抗HER2/neu-IgG3-IFN-α显示出对已建立的38C13/HER2肿瘤的有效活性，在用5 μ g融合蛋白每日三次剂量治疗的小鼠中观察到38%的肿瘤完全缓解（p = 0.0001）。Ab介导的IFN-α靶向诱导淋巴瘤细胞的生长停滞和凋亡，有助于抗肿瘤作用。该融合蛋白也具有比rIFN-α更长的体内半衰期。提示IFN-α Ab融合蛋白对B细胞淋巴瘤有治疗作用。
IFN-alpha, a cytokine crucial for the innate immune response, also demonstrates antitumor activity. However, use of IFN-alpha as an anticancer drug is hampered by its short half-life and toxicity. One approach to improving IFN-alpha's therapeutic index is to increase its half-life and tumor localization by fusing it to a tumor-specific Ab. In the present study, we constructed a fusion protein consisting of anti-HER2/neu-IgG3 and IFN-alpha (anti-HER2/neu-IgG3-IFN-alpha) and investigated its effect on a murine B cell lymphoma, 38C13, expressing human HER2/neu. Anti-HER2/neu-IgG3-IFN-alpha exhibited potent inhibition of 38C13/HER2 tumor growth in vivo. Administration of three daily 1-mu g doses of anti-HER2/neu-IgG3-IFN-alpha beginning 1 day after tumor challenge resulted in 88% of the mice remaining tumor free. Remarkably, anti-HER2/neu-IgG3-IFN-alpha demonstrated potent activity against established 38C13/HER2 tumors, with complete tumor remission observed in 38% of the mice treated with three daily doses of 5 mu g of the fusion protein (p = 0.0001). Ab-mediated targeting of IFN-alpha induced growth arrest and apoptosis of lymphoma cells contributing to the antitumor effect. The fusion protein also had a longer in vivo half-life than rIFN-alpha. These results suggest that IFN-alpha Ab fusion proteins maybe effective in the treatment of B cell lymphoma.