Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab

S. Michael Chin (), Christopher R. Kimberlin, Zygy Roe-Zurz, Pamela Zhang, Allison Xu, Sindy Liao-Chan, Debasish Sen, Andrew R. Nager, Nicole Schirle Oakdale, Colleen Brown, Feng Wang, Yuting Yang, Kevin Lindquist, Yik Andy Yeung, Shahram Salek-Ardakani and Javier Chaparro-Riggers ()
Additional contact information
S. Michael Chin: Cancer Immunology Discovery, Pfizer Inc.
Christopher R. Kimberlin: Cancer Immunology Discovery, Pfizer Inc.
Zygy Roe-Zurz: Cancer Immunology Discovery, Pfizer Inc.
Pamela Zhang: Cancer Immunology Discovery, Pfizer Inc.
Allison Xu: Cancer Immunology Discovery, Pfizer Inc.
Sindy Liao-Chan: Cancer Immunology Discovery, Pfizer Inc.
Debasish Sen: Cancer Immunology Discovery, Pfizer Inc.
Andrew R. Nager: Cancer Immunology Discovery, Pfizer Inc.
Nicole Schirle Oakdale: Cancer Immunology Discovery, Pfizer Inc.
Colleen Brown: Cancer Immunology Discovery, Pfizer Inc.
Feng Wang: Cancer Immunology Discovery, Pfizer Inc.
Yuting Yang: Department of Anesthesiology, University of Michigan
Kevin Lindquist: Cancer Immunology Discovery, Pfizer Inc.
Yik Andy Yeung: Cancer Immunology Discovery, Pfizer Inc.
Shahram Salek-Ardakani: Cancer Immunology Discovery, Pfizer Inc.
Javier Chaparro-Riggers: Cancer Immunology Discovery, Pfizer Inc.

Nature Communications, 2018, vol. 9, issue 1, 1-13

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.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-07136-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07136-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-07136-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().