6W3H

Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys

6W3H の概要

• エントリーDOI: 10.2210/pdb6w3h/pdb
• 分子名称: ATV Fc, Transferrin receptor protein 1,Transferrin receptor protein 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• 機能のキーワード: blood-brain barrier, transferrin binding receptor, antibody transport vehicle, protein transport
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 88381.44

構造登録者

Srivastava, A.,Kariolis, M.,Wells, R. (登録日: 2020-03-09, 公開日: 2020-06-10, 最終更新日: 2024-10-30)

主引用文献

Kariolis, M.S.,Wells, R.C.,Getz, J.A.,Kwan, W.,Mahon, C.S.,Tong, R.,Kim, D.J.,Srivastava, A.,Bedard, C.,Henne, K.R.,Giese, T.,Assimon, V.A.,Chen, X.,Zhang, Y.,Solanoy, H.,Jenkins, K.,Sanchez, P.E.,Kane, L.,Miyamoto, T.,Chew, K.S.,Pizzo, M.E.,Liang, N.,Calvert, M.E.K.,DeVos, S.L.,Baskaran, S.,Hall, S.,Sweeney, Z.K.,Thorne, R.G.,Watts, R.J.,Dennis, M.S.,Silverman, A.P.,Zuchero, Y.J.Y.
Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys.
Sci Transl Med, 12:-, 2020

PubMed Abstract: Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB). We describe the development of a BBB transport vehicle (TV) comprising an engineered Fc fragment that exploits receptor-mediated transcytosis for CNS delivery of biotherapeutics by binding a highly expressed brain endothelial cell target. TVs were engineered using directed evolution to bind the apical domain of the human transferrin receptor (hTfR) without the use of amino acid insertions, deletions, or unnatural appendages. A crystal structure of the TV-TfR complex revealed the TV binding site to be away from transferrin and FcRn binding sites, which was further confirmed experimentally in vitro and in vivo. Recombinant expression of TVs fused to anti-β-secretase (BACE1) Fabs yielded antibody transport vehicle (ATV) molecules with native immunoglobulin G (IgG) structure and stability. Peripheral administration of anti-BACE1 ATVs to hTfR-engineered mice and cynomolgus monkeys resulted in substantially improved CNS uptake and sustained pharmacodynamic responses. The TV platform readily accommodates numerous additional configurations, including bispecific antibodies and protein fusions, yielding a highly modular CNS delivery platform.

PubMed: 32461332
DOI: 10.1126/scitranslmed.aay1359

実験手法

X-RAY DIFFRACTION (3.38 Å)