6MI2

Structure of the human 4-1BB / Utomilumab Fab complex

Summary for 6MI2

• Entry DOI: 10.2210/pdb6mi2/pdb
• Related: 6MGE 6MGP 6MHR
• Descriptor: Utomilumab Fab heavy chain, Utomilumab Fab lambda chain, Tumor necrosis factor receptor superfamily member 9, ... (8 entities in total)
• Functional Keywords: signaling, tnfrsf, 4-1bb, cd137, immune system, therapeutic antibody, complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 129703.47

Authors

Kimberlin, C.R.,Chin, S.M.,Roe-Zurz, Z.,Xu, A.,Yang, Y. (deposition date: 2018-09-19, release date: 2018-11-21, Last modification date: 2024-11-13)

Primary citation

Chin, S.M.,Kimberlin, C.R.,Roe-Zurz, Z.,Zhang, P.,Xu, A.,Liao-Chan, S.,Sen, D.,Nager, A.R.,Oakdale, N.S.,Brown, C.,Wang, F.,Yang, Y.,Lindquist, K.,Yeung, Y.A.,Salek-Ardakani, S.,Chaparro-Riggers, J.
Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab.
Nat Commun, 9:4679-4679, 2018

PubMed 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.

PubMed: 30410017
DOI: 10.1038/s41467-018-07136-7

Experimental method

X-RAY DIFFRACTION (2.72 Å)