7D85

Crystal structure of anti-ErbB3 Fab ISU104 in complex with human ErbB3 extracellular domain 3

Summary for 7D85

• Entry DOI: 10.2210/pdb7d85/pdb
• Descriptor: Receptor tyrosine-protein kinase erbB-3, Anti-ErbB3 Fab heavy chain, Anti-ErbB3 Fab light chain, ... (5 entities in total)
• Functional Keywords: transferase/immune system, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 138361.48

Authors

Yoo, Y.,Cho, H.S. (deposition date: 2020-10-07, release date: 2021-04-07, Last modification date: 2024-10-30)

Primary citation

Hong, M.,Yoo, Y.,Kim, M.,Kim, J.Y.,Cha, J.S.,Choi, M.K.,Kim, U.,Kim, K.,Sohn, Y.,Bae, D.,Cho, H.S.,Hong, S.B.
A Novel Therapeutic Anti-ErbB3, ISU104 Exhibits Potent Antitumorigenic Activity by Inhibiting Ligand Binding and ErbB3 Heterodimerization.
Mol.Cancer Ther., 20:1142-1152, 2021

PubMed Abstract: ErbB3, a member of the ErbB receptor family, is a potent mediator in the development and progression of cancer, and its activation plays pivotal roles in acquired resistance against anti-EGFR therapies and other standard-of-care therapies. Upon ligand (NRG1) binding, ErbB3 forms heterodimers with other ErbB proteins (i.e., EGFR and ErbB2), which allows activation of downstream PI3K/Akt signaling. In this study, we developed a fully human anti-ErbB3 antibody, named ISU104, as an anticancer agent. ISU104 binds potently and specifically to the domain 3 of ErbB3. The complex structure of ErbB3-domain 3::ISU104-Fab revealed that ISU104 binds to the NRG1 binding region of domain 3. The elucidated structure suggested that the binding of ISU104 to ErbB3 would hinder not only ligand binding but also the structural changes required for heterodimerization. Biochemical studies confirmed these predictions. ISU104 inhibited ligand binding, ligand-dependent heterodimerization and phosphorylation, and induced the internalization of ErbB3. As a result, downstream Akt phosphorylation and cell proliferation were inhibited. The anticancer efficacy of ISU104 was demonstrated in xenograft models of various cancers. In summary, a highly potent ErbB3 targeting antibody, ISU104, is suitable for clinical development.

PubMed: 33782100
DOI: 10.1158/1535-7163.MCT-20-0907

Experimental method

X-RAY DIFFRACTION (2.5 Å)