7YK4

ox40-antibody

Summary for 7YK4

• Entry DOI: 10.2210/pdb7yk4/pdb
• Descriptor: antibody-H, antibody-L, Tumor necrosis factor receptor superfamily member 4, ... (5 entities in total)
• Functional Keywords: ox40 and antibody complex, antitumor protein, antitumor protein-immune system complex, antitumor protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 132822.79

Authors

Zhou, A. (deposition date: 2022-07-21, release date: 2023-08-09, Last modification date: 2024-10-16)

Primary citation

Zhang, J.,Jiang, X.,Gao, H.,Zhang, F.,Zhang, X.,Zhou, A.,Xu, T.,Cai, H.
Structural Basis of a Novel Agonistic Anti-OX40 Antibody.
Biomolecules, 12:-, 2022

PubMed Abstract: Agonistic antibodies targeting co-stimulating receptor OX40 on T cells are considered as important as (or complementary to) the immune checkpoint blockers in cancer treatment. However, none of these agonistic antibodies have reached the late stage of clinical development partially due to the lack of intrinsic potency with the correlation between binding epitope and activity of the antibody not well understood. Here, we identified a novel anti-OX40 agonistic antibody DF004, which stimulated the proliferation of human CD4 T cells in vitro and inhibited tumor growth in a mouse model. Our crystallography structural studies showed that DF004 binds to the CRD2 region of OX40 while RG7888, an OX40 agonist antibody developed by Roche, binds to CRD3 of OX40 to the diametrically opposite position of DF004. This suggests that the agonistic activities of the antibodies are not necessarily epitope dependent. As their agonistic activities critically depend on clustering or cross-linking, our structural modeling indicates that the agonistic activity requires the optimal positioning of three Fc receptor/antibody/OX40 complexes on the cell membrane to facilitate the formation of one intracellular hexameric TRAF complex for downstream signal transduction, which is relatively inefficient. This may explain the lack of sufficient potency of these OX40 antibodies in a therapeutic setting and sheds light on the development of cross-linking-independent agonistic antibodies.

PubMed: 36139048
DOI: 10.3390/biom12091209

Experimental method

X-RAY DIFFRACTION (2.7 Å)