Research Article: Neural Stem Cells as a Novel Platform for Tumor-Specific Delivery of Therapeutic Antibodies

Date Published: December 15, 2009

Publisher: Public Library of Science

Author(s): Richard T. Frank, Marissa Edmiston, Stephen E. Kendall, Joseph Najbauer, Chia-Wei Cheung, Thewodros Kassa, Marianne Z. Metz, Seung U. Kim, Carlotta A. Glackin, Anna M. Wu, Paul J. Yazaki, Karen S. Aboody, Mikhail V. Blagosklonny.

Abstract: 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.

Partial Text: Recombinant monoclonal antibodies offer a targeted approach to cancer therapy and have substantially lower toxicity to normal cells than chemotherapy. However, their large molecular size and high affinity to antigens at the tumor border limit the ability of antibodies to deeply penetrate tumor foci [1]. Central nervous system (CNS) tumors pose a particular challenge for antibody therapeutics, because the blood-brain barrier (BBB) prevents intravenously-injected antibodies from reaching CNS metastases.

Overexpression of HER2 is a marker for poor prognosis in breast cancer and is often correlated with increased metastasis, including to the CNS [18], [19]. Trastuzumab directly inhibits the proliferation of HER2-overexpressing breast cancer cells and induces immune-mediated killing of target cancer cells through antibody-dependent cellular cytotoxicity [20]. However, trastuzumab is unable to cross the BBB, and therefore cannot be used to treat CNS metastases. Importantly, NSCs can target breast cancer metastasis in the brain [9] and can penetrate deep and hypoxic regions of solid tumors [7]. Therefore, we examined the feasibility of expressing therapeutic antibodies in tumor-tropic human NSCs, with the ultimate goal of using such NSCs as a platform for delivery of anti-HER2 antibody to otherwise inaccessible tumor foci.



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