Neural Stem Cells as a Novel Platform for Tumor-Specific Delivery of Therapeutic Antibodies
Neural Stem Cells as a Novel Platform for Tumor-Specific Delivery of Therapeutic Antibodies
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DOI：
10.1371/journal.pone.0008314
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发表时间：
2009-12-15
期刊：
影响因子：
3.7
通讯作者：
Aboody, Karen S.
中科院分区：
文献类型：
--
作者：
Frank, Richard T.;Edmiston, Marissa;Aboody, Karen S.
背景：重组单克隆抗体已成为癌症治疗的重要工具。尽管基于抗体的治疗显示出了希望，但抗体的大分子大小限制了它们有效穿透实体肿瘤的能力，并阻碍了有效穿过血脑屏障进入中枢神经系统（CNS）。因此，静脉注射抗体不能有效治疗血管化不良的实体瘤和中枢神经系统转移瘤。人类神经干细胞（NSCs）固有的致瘤性可以被潜在地利用来克服这些障碍并显著改善癌症免疫治疗。静脉给药的NSCs优先迁移到中枢神经系统内外的原发性和转移性肿瘤部位。因此，我们假设NSCs可以作为靶向恶性肿瘤抗体的理想细胞递送平台。方法和发现：作为概念验证，我们选择了赫赛汀（TM）（曲妥珠单抗），这是一种广泛用于治疗her2过表达乳腺癌的单克隆抗体。HER2在乳腺癌中的过表达与中枢神经系统转移高度相关，而中枢神经系统转移是曲妥珠单抗治疗无法达到的。因此，nsc介导的给药可能会提高曲妥珠单抗的治疗效果。在这里，我们首次报道了人类NSCs可以通过基因修饰分泌抗her2免疫球蛋白分子。这些nsc分泌的抗体组装正确，具有肿瘤细胞结合亲和力和特异性，在体外可有效抑制her2过表达乳腺癌细胞的增殖。我们还证明了分泌免疫球蛋白的NSCs在体内表现出对肿瘤细胞的偏好，并且可以在小鼠体内传递针对人类乳腺癌异种移植物的抗体。综上所述，这些结果表明，经修饰后可分泌her2靶向抗体的NSCs为靶向癌症免疫治疗提供了一个有前景的新平台。具体来说，这种nsc介导的抗体递送系统有可能显著改善her2过表达乳腺癌患者的临床结果。
Background: Recombinant monoclonal antibodies have emerged as important tools for cancer therapy. Despite the promise shown by antibody-based therapies, the large molecular size of antibodies limits their ability to efficiently penetrate solid tumors and precludes efficient crossing of the blood-brain-barrier into the central nervous system (CNS). Consequently, poorly vascularized solid tumors and CNS metastases cannot be effectively treated by intravenously-injected antibodies. The inherent tumor-tropic properties of human neural stem cells (NSCs) can potentially be harnessed to overcome these obstacles and significantly improve cancer immunotherapy. Intravenously-delivered NSCs preferentially migrate to primary and metastatic tumor sites within and outside the CNS. Therefore, we hypothesized that NSCs could serve as an ideal cellular delivery platform for targeting antibodies to malignant tumors.Methods and Findings: As proof-of-concept, we selected Herceptin(TM) (trastuzumab), a monoclonal antibody widely used to treat HER2-overexpressing breast cancer. HER2 overexpression in breast cancer is highly correlated with CNS metastases, which are inaccessible to trastuzumab therapy. Therefore, NSC-mediated delivery of trastuzumab may improve its therapeutic efficacy. Here we report, for the first time, that human NSCs can be genetically modified to secrete anti-HER2 immunoglobulin molecules. These NSC-secreted antibodies assemble properly, possess tumor cell-binding affinity and specificity, and can effectively inhibit the proliferation of HER2-overexpressing breast cancer cells in vitro. We also demonstrate that immunoglobulin-secreting NSCs exhibit preferential tropism to tumor cells in vivo, and can deliver antibodies to human breast cancer xenografts in mice.Conclusions: Taken together, these results suggest that NSCs modified to secrete HER2-targeting antibodies constitute a promising novel platform for targeted cancer immunotherapy. Specifically, this NSC-mediated antibody delivery system has the potential to significantly improve clinical outcome for patients with HER2-overexpressing breast cancer.