9GFD

Crystal structure of ASO binding Fab fragment with ASO139

これはPDB形式変換不可エントリーです。

9GFD の概要

• エントリーDOI: 10.2210/pdb9gfd/pdb
• 分子名称: Fab fragment heavy chain, Fab Fragment light chain, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: antibody, fab fragment, aso, immune system
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49438.80

構造登録者

Hsia, H.-E.,Zanini, C.,Simonneau, C.,Fraidling, J.,Kraft, T.,Mayer, K.,Sommer, A.,Indlekofer, A.,Wirth, T.,Benz, J.,Geroges, G.,Langer, M.L.,Gassner, C.,Larraillet, V.,Manso, M.,Ravn, J.,Hofer, K.,Emrich, T.,Niewoehner, J.,Schumacher, F.,Brinkmann, U. (登録日: 2024-08-09, 公開日: 2025-08-20, 最終更新日: 2025-11-12)

主引用文献

Hsia, H.E.,Zanini, C.,Simonneau, C.,Fraidling, J.,Kraft, T.E.,Mayer, K.,Sommer, A.,Indlekofer, A.,Wirth, T.,Benz, J.,Georges, G.,Langer, L.M.,Gassner, C.,Larraillet, V.,Lohmann, S.,Koller, E.,Manso, M.,Ravn, J.,Hofer, K.,Emrich, T.,Niewohner, J.,Schumacher, F.,Brinkmann, U.
Improved targeted delivery of antisense oligonucleotide with an antibody mask.
Nucleic Acids Res., 53:-, 2025

PubMed Abstract: Antisense oligonucleotides (ASOs) are synthetic nucleic acid strands designed to modulate gene expression by binding to RNA transcripts. In brain diseases, transferrin receptor (TfR)-targeting antibody-ASO conjugates have shown promise for brain delivery of ASOs via transcytosis in preclinical studies. This enables the more patient friendly intravenous or subcutaneous administration of the compounds. However, these conjugates can exhibit faster plasma clearance and different peripheral pharmacokinetic profiles due to ASO modifications, such as phosphorothioate (PS) linkages and locked nucleic acids (LNAs). In this study, we employed an antibody recognizing LNA- and PS-modified ASOs independent of the base sequences as a cloaking module to mitigate these issues. Using Kutzneria albida transglutaminase (KTG) technology and click chemistry, we generated TfR antibody-ASO conjugates with covalently or noncovalently incorporated ASO binders. Additionally, a noncovalent carrier antibody approach was explored. These conjugates and complexes with additional ASO binder(s) show improved TfR-targeted cellular uptake, undergo transcytosis in cellular blood-brain barrier models, show less nonspecific cellular accumulation, and anticipated ASO activity.

PubMed: 41166443
DOI: 10.1093/nar/gkaf487

実験手法

X-RAY DIFFRACTION (1.43 Å)