6OGX

Ternary complex of OX40R (TNFRSF4) bound to Fab1 and Fab2

6OGX の概要

• エントリーDOI: 10.2210/pdb6ogx/pdb
• 分子名称: Fab 1 Heavy Chain, Fab1 Light Chain, Tumor necrosis factor receptor superfamily member 4, ... (7 entities in total)
• 機能のキーワード: tnfrsf4, cd134, ox40r, 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: 5
• 化学式量合計: 112763.66

構造登録者

Ultsch, M.H.,Boenig, G.,Harris, S.F. (登録日: 2019-04-03, 公開日: 2019-07-10, 最終更新日: 2024-11-06)

主引用文献

Yang, Y.,Yeh, S.H.,Madireddi, S.,Matochko, W.L.,Gu, C.,Pacheco Sanchez, P.,Ultsch, M.,De Leon Boenig, G.,Harris, S.F.,Leonard, B.,Scales, S.J.,Zhu, J.W.,Christensen, E.,Hang, J.Q.,Brezski, R.J.,Marsters, S.,Ashkenazi, A.,Sukumaran, S.,Chiu, H.,Cubas, R.,Kim, J.M.,Lazar, G.A.
Tetravalent biepitopic targeting enables intrinsic antibody agonism of tumor necrosis factor receptor superfamily members.
Mabs, 11:996-1011, 2019

PubMed Abstract: Agonism of members of the tumor necrosis factor receptor superfamily (TNFRSF) with monoclonal antibodies is of high therapeutic interest due to their role in immune regulation and cell proliferation. A major hurdle for pharmacologic activation of this receptor class is the requirement for high-order clustering, a mechanism that imposes a reliance on Fc receptor-mediated crosslinking. This extrinsic dependence represents a potential limitation of virtually the entire pipeline of agonist TNFRSF antibody drugs, of which none have thus far been approved or reached late-stage clinical trials. We show that tetravalent biepitopic targeting enables robust intrinsic antibody agonism for two members of this family, OX40 and DR5, that is superior to extrinsically crosslinked native parental antibodies. Tetravalent biepitopic anti-OX40 engagement co-stimulated OX40 cells, obviated the requirement for CD28 co-signal for T cell activation, and enabled superior pharmacodynamic activity relative to native IgG in a murine vaccination model. This work establishes a proof of concept for an engineering approach that addresses a major gap for the therapeutic activation of this important receptor class.

PubMed: 31156033
DOI: 10.1080/19420862.2019.1625662

実験手法

X-RAY DIFFRACTION (2.77 Å)