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.
Bibliographical noteFunding Information:
H.-S. Cho was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (NRF-2016R1A5A1010764, NRF-2017M3A9F6029755, and NRF-2019M3E5D6063903), the Strategic Initiative for Microbiomes in Agriculture and Food grant funded by the Ministry of Agriculture, Food and Rural Affairs (918012-4), and a grant funded by ISU ABXIS Co. Ltd. M. Hong, M. Kim, K. Kim, Y. Sohn, and D. Bae were supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI16C0528). We thank the staff scientists for assistance with the Beamline 11C at the Pohang Light Source, Pohang Accelerator Laboratory.
© 2021 American Association for Cancer Research.
All Science Journal Classification (ASJC) codes
- Cancer Research