7JKB

2xVH Fab

7JKB の概要

• エントリーDOI: 10.2210/pdb7jkb/pdb
• 分子名称: Anti-lysozyme, Anti-Her2 (3 entities in total)
• 機能のキーワード: antibody, 2xvh, fab, immune system
• 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: 49698.45

構造登録者

Lord, D.M.,Zhou, Y.F. (登録日: 2020-07-28, 公開日: 2020-11-25, 最終更新日: 2024-10-23)

主引用文献

Ramasubramanian, A.,Tennyson, R.,Magnay, M.,Kathuria, S.,Travaline, T.,Jain, A.,Lord, D.M.,Salemi, M.,Sullivan, C.,Magnay, T.,Hu, J.,Bric-Furlong, E.,Rival, P.,Zhou, Y.,Hoffmann, D.,Brondyk, W.,Radosevic, K.,Chowdhury, P.S.
Bringing the Heavy Chain to Light: Creating a Symmetric, Bivalent IgG-Like Bispecific.
Antibodies, 9:-, 2020

PubMed Abstract: Bispecific molecules are biologically significant, yet their complex structures pose important manufacturing and pharmacokinetic challenges. Nevertheless, owing to similarities with monoclonal antibodies (mAbs), IgG-like bispecifics conceptually align well with conventional expression and manufacturing platforms and often exhibit potentially favorable drug metabolism and pharmacokinetic (DMPK) properties. However, IgG-like bispecifics do not possess target bivalency and current designs often require tedious engineering and purification to ensure appropriate chain pairing. Here, we present a near-native IgG antibody format, the 2xVH, which can create bivalency for each target or epitope and requires no engineering for cognate chain pairing. In this modality, two different variable heavy (VH) domains with distinct binding specificities are grafted onto the first constant heavy (CH1) and constant light (CL) domains, conferring the molecule with dual specificity. To determine the versatility of this format, we characterized the expression, binding, and stability of several previously identified soluble human VH domains. By grafting these domains onto an IgG scaffold, we generated several prototype 2xVH IgG and Fab molecules that display similar properties to mAbs. These molecules avoided the post-expression purification necessary for engineered bispecifics while maintaining a capacity for simultaneous dual binding. Hence, the 2xVH format represents a bivalent, bispecific design that addresses limitations of manufacturing IgG-like bispecifics while promoting biologically-relevant dual target engagement.

PubMed: 33172091
DOI: 10.3390/antib9040062

実験手法

X-RAY DIFFRACTION (2.55 Å)