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 04:00:00 UTC 2018 · Nature Communications

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

Chin, S. Michael ^[1]; Kimberlin, Christopher R. ^[2]; Roe-Zurz, Zygy ^[3]; Zhang, Pamela ^[2]; Xu, Allison ^[2]; Liao-Chan, Sindy ^[2]; Sen, Debasish ^[2]; Nager, Andrew R. ^[2]; Oakdale, Nicole Schirle ^[2]; Brown, Colleen ^[2]; Wang, Feng ^[4]; Yang, Yuting ^[5]; Lindquist, Kevin ^[2]; Yeung, Yik Andy ^[2]; Salek-Ardakani, Shahram ^[2]; Chaparro-Riggers, Javier ^[2]

Cancer Immunology Discovery, South San Francisco, CA (United States); DOE/OSTI
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, Journal Name: Nature Communications Journal Issue: 1 Vol. 9; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Routes of Delivery for CpG and Anti-CD137 for the Treatment of Orthotopic Kidney Tumors in Mice Westwood, Jennifer A.; Potdevin Hunnam, Titaina C. U.; Pegram, Hollie J. PLoS ONE, Vol. 9, Issue 5 https://doi.org/10.1371/journal.pone.0095847	journal	May 2014
Focal Radiation Therapy Combined with 4-1BB Activation and CTLA-4 Blockade Yields Long-Term Survival and a Protective Antigen-Specific Memory Response in a Murine Glioma Model Belcaid, Zineb; Phallen, Jillian A.; Zeng, Jing PLoS ONE, Vol. 9, Issue 7 https://doi.org/10.1371/journal.pone.0101764	journal	July 2014
Reinvigorating Exhausted T Cells by Blockade of the PD-1 Pathway Lee, Junghwa; Ahn, Eunseon; Kissick, Haydn T. Forum on Immunopathological Diseases and Therapeutics, Vol. 6, Issue 1-2 https://doi.org/10.1615/ForumImmunDisTher.2015014188	journal	January 2015
4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity Bartkowiak, Todd; Curran, Michael A. Frontiers in Oncology, Vol. 5 https://doi.org/10.3389/fonc.2015.00117	journal	June 2015
Functional Characteristics of the High Affinity IgG Receptor, FcγRI van der Poel, Cees E.; Spaapen, Robbert M.; van de Winkel, Jan G. J. The Journal of Immunology, Vol. 186, Issue 5 https://doi.org/10.4049/jimmunol.1003526	journal	February 2011
Soluble CD137 (4-1BB) Ligand Is Released Following Leukocyte Activation and Is Found in Sera of Patients with Hematological Malignancies Salih, Helmut R.; Schmetzer, Helga M.; Burke, Christine The Journal of Immunology, Vol. 167, Issue 7 https://doi.org/10.4049/jimmunol.167.7.4059	journal	October 2001
ERK-Dependent Bim Modulation Downstream of the 4-1BB-TRAF1 Signaling Axis Is a Critical Mediator of CD8 T Cell Survival In Vivo Sabbagh, Laurent; Pulle, Gayle; Liu, Yuanqing The Journal of Immunology, Vol. 180, Issue 12 https://doi.org/10.4049/jimmunol.180.12.8093	journal	June 2008

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Antibody-mediated targeting of TNFR2 activates CD8 ⁺ T cells in mice and promotes antitumor immunity Tam, Eric M.; Fulton, Ross B.; Sampson, James F. Science Translational Medicine, Vol. 11, Issue 512 https://doi.org/10.1126/scitranslmed.aax0720	journal	October 2019
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