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-Structure paper
タイトル | Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control. |
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ジャーナル・号・ページ | Nat Commun, Vol. 9, Issue 1, Page 450, Year 2018 |
掲載日 | 2018年1月31日 |
著者 | Markus Schmid / Patrick Ernst / Annemarie Honegger / Maarit Suomalainen / Martina Zimmermann / Lukas Braun / Sarah Stauffer / Cristian Thom / Birgit Dreier / Matthias Eibauer / Anja Kipar / Viola Vogel / Urs F Greber / Ohad Medalia / Andreas Plückthun / |
PubMed 要旨 | Most systemic viral gene therapies have been limited by sequestration and degradation of virions, innate and adaptive immunity, and silencing of therapeutic genes within the target cells. Here we ...Most systemic viral gene therapies have been limited by sequestration and degradation of virions, innate and adaptive immunity, and silencing of therapeutic genes within the target cells. Here we engineer a high-affinity protein coat, shielding the most commonly used vector in clinical gene therapy, human adenovirus type 5. Using electron microscopy and crystallography we demonstrate a massive coverage of the virion surface through the hexon-shielding scFv fragment, trimerized to exploit the hexon symmetry and gain avidity. The shield reduces virion clearance in the liver. When the shielded particles are equipped with adaptor proteins, the virions deliver their payload genes into human cancer cells expressing HER2 or EGFR. The combination of shield and adapter also increases viral gene delivery to xenografted tumors in vivo, reduces liver off-targeting and immune neutralization. Our study highlights the power of protein engineering for viral vectors overcoming the challenges of local and systemic viral gene therapies. |
リンク | Nat Commun / PubMed:29386504 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.8 - 7.4 Å |
構造データ | EMDB-3821: Cryo-EM reconstruction of a modified human Adenovirus C5 PDB-5ogi: |
化合物 | ChemComp-SO4: ChemComp-DIO: ChemComp-EDO: ChemComp-MES: ChemComp-HOH: |
由来 |
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キーワード | VIRAL PROTEIN / Antibody / Human Adenovirus C5 / gene therapy / gene therapy Viral Protein |