4UB0

New design for monovalent bispecific IgG through cysteine engineering of the CH1-CL interface

4UB0 の概要

• エントリーDOI: 10.2210/pdb4ub0/pdb
• 分子名称: IgG1, heavy chain, IgG1, light chain (3 entities in total)
• 機能のキーワード: fab, knobs-into-holes, bispecific, 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: 46847.18

構造登録者

Oganesyan, V.Y.,Dall'Acqua, W.F. (登録日: 2014-08-11, 公開日: 2015-07-15, 最終更新日: 2024-11-13)

主引用文献

Mazor, Y.,Oganesyan, V.,Yang, C.,Hansen, A.,Wang, J.,Liu, H.,Sachsenmeier, K.,Carlson, M.,Gadre, D.V.,Borrok, M.J.,Yu, X.Q.,Dall'Acqua, W.,Wu, H.,Chowdhury, P.S.
Improving target cell specificity using a novel monovalent bispecific IgG design.
Mabs, 7:377-389, 2015

PubMed Abstract: Monovalent bispecific IgGs cater to a distinct set of mechanisms of action but are difficult to engineer and manufacture because of complexities associated with correct heavy and light chain pairing. We have created a novel design, "DuetMab," for efficient production of these molecules. The platform uses knobs-into-holes (KIH) technology for heterodimerization of 2 distinct heavy chains and increases the efficiency of cognate heavy and light chain pairing by replacing the native disulfide bond in one of the CH1-CL interfaces with an engineered disulfide bond. Using two pairs of antibodies, cetuximab (anti-EGFR) and trastuzumab (anti-HER2), and anti-CD40 and anti-CD70 antibodies, we demonstrate that DuetMab antibodies can be produced in a highly purified and active form, and show for the first time that monovalent bispecific IgGs can concurrently bind both antigens on the same cell. This last property compensates for the loss of avidity brought about by monovalency and improves selectivity toward the target cell.

PubMed: 25621507
DOI: 10.1080/19420862.2015.1007816

実験手法

X-RAY DIFFRACTION (2.2 Å)