EGFR-Targeting Nanobodies Released by Stem Cells Reduce Tumor Growth

EGF receptor (EGFR) is amplified or mutated in a large percentage of glioblastoma, but treatment with anti-EGFR monoclonal antibodies has been largely unsuccessful, in part due to the blood–brain barrier. An alternative approach is the use of EGFR-specific nanobodies, which are smaller antibody fragments that consist of only the antigen-targeting domain, provide increased tissue penetration, and have been shown to block EGF binding to EGFR. To further investigate nanobodies as a treatment for glioblastoma, van de Water and colleagues engineered secretable, bivalent versions of EGFR-targeting nanobodies (ENb) and expressed them in neural stem cells (NSC), which specifically migrate to brain tumors and may therefore improve therapeutic delivery. ENbs were efficiently secreted by NSCs and prevented ligand stimulation of EGFR-expressing glioblastoma cells in vitro, thereby inhibiting the activation of downstream signaling and reducing glioblastoma cell viability. ENbs fused to fluorescent or bioluminescent imaging modalities retained the ability to prevent EGFR activation and showed the sustained localization of NSC-secreted ENbs to glioblastoma tumors, in contrast with systemically delivered ENbs that also localized to the liver and kidney, indicating that these fusions may be useful for tumor imaging. Furthermore, NSC-secreted ENbs immunoconjugated to the proapoptotic protein TRAIL diminished cell viability and induced caspasedependent apoptosis in glioblastoma cell lines with varying resistance to TRAIL, suggesting that ENb–TRAIL fusions may target a broad spectrum of tumor cells. Importantly, intratumoral implantation of NSCs expressing ENbs significantly reduced the growth of established intracranial glioblastomas and suppressed the invasion of primary glioblastoma xenograft tumors; expression of ENb–TRAIL augmented these inhibitory effects and further prolonged the survival of tumor-bearing mice. These results support clinical testing of tumor-specific delivery of anti-EGFR nanobodies as a therapeutic approach for the treatment of glioblastoma.

van de Water JA, Bagci-Onder T, Agarwal AS, Wakimoto H, Roovers RC, Zhu Y, et al. Therapeutic stem cells expressing variants of EGFR-specific nanobodies have antitumor effects. Proc Natl Acad Sci U S A 2012;109:16642–7.

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