Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Chin, S.; Kimberlin, Christopher; Roe-Zurz, Zygy; Zhang, Pamela; Xu, Allison; Liao-Chan, Sindy; Sen, Debasish; Nager, Andrew; Oakdale, Nicole; Brown, Colleen; Wang, Feng; Yang, Yuting; Lindquist, Kevin; Yeung, Yik; Salek-Ardakani, Shahram; Chaparro-Riggers, Javier
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 13
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-07136-7
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract 4-1BB (CD137, TNFRSF9 ) is an inducible costimulatory receptor expressed on activated T cells. Clinical trials of two agonist antibodies, utomilumab (PF-05082566) and urelumab (BMS-663513), are ongoing in multiple cancer indications, and both antibodies demonstrate distinct activities in the clinic. To understand these differences, we solved structures of the human 4-1BB/4-1BBL complex, the 4-1BBL trimer alone, and 4-1BB bound to utomilumab or urelumab. The 4-1BB/4-1BBL complex displays a unique interaction between receptor and ligand when compared with other TNF family members. Furthermore, our ligand-only structure differs from previously published data. Utomilumab, a ligand-blocking antibody, binds 4-1BB between CRDs 3 and 4. In contrast, urelumab binds 4-1BB CRD-1, away from the ligand binding site. Finally, cell-based assays demonstrate utomilumab is a milder agonist than urelumab. Collectively, our data provide a deeper understanding of the 4-1BB signaling complex, providing a template for future development of next generation 4-1BB targeted biologics. The costimulatory T-cell receptor 4-1BB is an immuno-oncology target. Here the authors present the ligand bound 4-1BB receptor crystal structure in addition to the structures of 4-1BB bound with two therapeutic antibodies and verify the antibody binding sites by mutational analysis, which is of interest for further 4-1BB therapeutics development.