8G0M

Structure of complex between TV6.6 and CD98hc ECD

8G0M の概要

• エントリーDOI: 10.2210/pdb8g0m/pdb
• 分子名称: 4F2 cell-surface antigen heavy chain, TV 6.6 Fc fragment, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: transport vehicle, transport protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 74635.94

構造登録者

Kariolis, M.S.,Lexa, K.,Liau, N.P.D.,Srivastava, D.,Tran, H.,Wells, R.C. (登録日: 2023-01-31, 公開日: 2023-10-18, 最終更新日: 2024-11-06)

主引用文献

Chew, K.S.,Wells, R.C.,Moshkforoush, A.,Chan, D.,Lechtenberg, K.J.,Tran, H.L.,Chow, J.,Kim, D.J.,Robles-Colmenares, Y.,Srivastava, D.B.,Tong, R.K.,Tong, M.,Xa, K.,Yang, A.,Zhou, Y.,Akkapeddi, P.,Annamalai, L.,Bajc, K.,Blanchette, M.,Cherf, G.M.,Earr, T.K.,Gill, A.,Huynh, D.,Joy, D.,Knight, K.N.,Lac, D.,Leung, A.W.,Lexa, K.W.,Liau, N.P.D.,Becerra, I.,Malfavon, M.,McInnes, J.,Nguyen, H.N.,Lozano, E.I.,Pizzo, M.E.,Roche, E.,Sacayon, P.,Calvert, M.E.K.,Daneman, R.,Dennis, M.S.,Duque, J.,Gadkar, K.,Lewcock, J.W.,Mahon, C.S.,Meisner, R.,Solanoy, H.,Thorne, R.G.,Watts, R.J.,Zuchero, Y.J.Y.,Kariolis, M.S.
CD98hc is a target for brain delivery of biotherapeutics.
Nat Commun, 14:5053-5053, 2023

PubMed Abstract: Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TV). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATV) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATV demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATV that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TV as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

PubMed: 37598178
DOI: 10.1038/s41467-023-40681-4

実験手法

X-RAY DIFFRACTION (2.25 Å)