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A novel single-chain antibody redirects adenovirus to IL13R?2-expressing brain tumors.

ABSTRACT: The generation of a targeting agent that strictly binds to IL13R?2 will significantly expand the therapeutic potential for the treatment of IL13R?2-expressing cancers. In order to fulfill this goal, we generated a single-chain antibody (scFv47) from our parental IL13R?2 monoclonal antibody and tested its binding properties. Furthermore, to demonstrate the potential therapeutic applicability of scFv47, we engineered an adenovirus by incorporating scFv47 as the targeting moiety in the viral fiber and characterized its properties in vitro and in vivo. The scFv47 binds to human recombinant IL13R?2, but not to IL13R?1 with a high affinity of 0.9 · 10(-9) M, similar to that of the parental antibody. Moreover, the scFv47 successfully redirects adenovirus to IL13R?2 expressing glioma cells both in vitro and in vivo. Our data validate scFv47 as a highly selective IL13R?2 targeting agent and justify further development of scFv47-modified oncolytic adenovirus and other therapeutics for the treatment of IL13R?2-expressing glioma and other malignancies.

SUBMITTER: Kim JW

PROVIDER: S-EPMC4677343 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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A novel single-chain antibody redirects adenovirus to IL13Rα2-expressing brain tumors.

Kim Julius W JW Young Jacob S JS Solomaha Elena E Kanojia Deepak D Lesniak Maciej S MS Balyasnikova Irina V IV

Scientific reports 20151214

The generation of a targeting agent that strictly binds to IL13Rα2 will significantly expand the therapeutic potential for the treatment of IL13Rα2-expressing cancers. In order to fulfill this goal, we generated a single-chain antibody (scFv47) from our parental IL13Rα2 monoclonal antibody and tested its binding properties. Furthermore, to demonstrate the potential therapeutic applicability of scFv47, we engineered an adenovirus by incorporating scFv47 as the targeting moiety in the viral fiber ...[more]

PMID: 26656559

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Project description:Rationale: Antiretroviral therapy can effectively suppress HIV-1 replication in the peripheral blood to an undetectable level. However, elimination of the latent virus in reservoirs remains a challenge and is a major obstacle in the treatment of HIV-1-infected patients. Exosomes exhibit huge promise as an endogenous drug delivery nanosystem for delivering drugs to solid tissues given their unique properties, including low immunogenicity, innate stability, high delivery efficiency, and most importantly the ability to penetrate solid tissues due to their lipophilic properties. Methods: We engineered and expressed the scFv of a high affinity HIV-1-specific monoclonal antibody, 10E8, on the exosomal surface (10E8scFv-exos). Subsequently, the 10E8scFv-exos were loaded with curcumin (Cur), a chemical that kills HIV-1-infected cells, or miR-143, an apoptosis-inducing miRNA. We tested the ability of 10E8scFv-exos to deliver cargo to Env+ target cells and tissues, as well as their ability to suppress HIV-1 infection. Results: 10E8scFv-exos efficiently targeted CHO cells expressing a trimeric gp140 on their surface (Env+ cells) in vitro, as demonstrated by confocal imaging and flow cytometry. 10E8scFv-exos loaded with Cur or miR-143 showed specific killing of Env+ cells. In addition, 10E8scFv-exos loaded with Cur or miR-143 could suppress p24 expression in an HIV-1 latency cell line ACH2 and in PBMCs from an ART-treated HIV-1-infected patient. In an NCG mouse model grafted with tumorigenic Env+ CHO cells and which had developed solid tissue tumors, intravenously injected 10E8scFv-exos targeted the Env-expressing tissues and delivered Cur to induce a strong suppression of the Env+ tumor growth with low toxicity. Conclusion: In principle, engineered exosomes can deliver anti-HIV agents to solid tissues by specifically targeting cells expressing viral envelop proteins and inducing cell killing, suggesting that such an approach could be developed for eradicating virus-infected cells in tissue reservoirs.

Dataset Information

A novel single-chain antibody redirects adenovirus to IL13R?2-expressing brain tumors.

Publications

A novel single-chain antibody redirects adenovirus to IL13Rα2-expressing brain tumors.

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