6OKM

Human OX40R (TNFRSF4) bound to Fab 3C8

Summary for 6OKM

• Entry DOI: 10.2210/pdb6okm/pdb
• Related: 6OGX
• Descriptor: Fab 3C8 Heavy Chain, Fab 3C8 light chain, Tumor necrosis factor receptor superfamily member 4, ... (4 entities in total)
• Functional Keywords: ox40, tnfrsf4, fab, receptor, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 64805.26

Authors

Boenig, G.,Ultsch, M.H.,Harris, S.F. (deposition date: 2019-04-14, release date: 2019-08-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)