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

Chin, S. Michael; Kimberlin, Christopher R.; Roe-Zurz, Zygy; Zhang, Pamela; Xu, Allison; Liao-Chan, Sindy; Sen, Debasish; Nager, Andrew R.; Oakdale, Nicole Schirle; Brown, Colleen; Wang, Feng; Yang, Yuting; Lindquist, Kevin; Yeung, Yik Andy; Salek-Ardakani, Shahram; Chaparro-Riggers, Javier

doi:10.1038/s41467-018-07136-7

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

Journal Article · Thu Nov 08 00:00:00 EST 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-07136-7· OSTI ID:1624124

Chin, S. Michael ^[1]; Kimberlin, Christopher R. ^[1]; Roe-Zurz, Zygy ^[2]; Zhang, Pamela ^[1]; Xu, Allison ^[1]; Liao-Chan, Sindy ^[1]; Sen, Debasish ^[1]; Nager, Andrew R. ^[1]; Oakdale, Nicole Schirle ^[1]; Brown, Colleen ^[1]; Wang, Feng ^[3]; Yang, Yuting ^[4]; Lindquist, Kevin ^[1]; Yeung, Yik Andy ^[1]; Salek-Ardakani, Shahram ^[1]; Chaparro-Riggers, Javier ^[1]

Cancer Immunology Discovery, South San Francisco, CA (United States)
Cancer Immunology Discovery, South San Francisco, CA (United States); Israel Institute of Technology, Haifa (Israel)
Cancer Immunology Discovery, South San Francisco, CA (United States); Bristol-Myers Squibb, Redwood City, CA (United States)
Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Anesthesiology

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1624124

Journal Information:: Nature Communications, Vol. 9, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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