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Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab.
Nat Commun. 2018 11 08; 9(1):4679.NC

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.

Authors+Show Affiliations

Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA. shermanmichael.chin@pfizer.com.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA. Technion - Israel Institute of Technology, Haifa, 3200003, Israel.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA. Bristol-Myers Squibb, 700 Bay Rd, Redwood City, CA, 94063, USA.Department of Anesthesiology, University of Michigan, Ann Arbor, MI, 48105, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA.Cancer Immunology Discovery, Pfizer Inc., 230 E. Grand Ave, South San Francisco, CA, 94080, USA. javier.chaparro-riggers@pfizer.com.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30410017

Citation

Chin, S Michael, et al. "Structure of the 4-1BB/4-1BBL Complex and Distinct Binding and Functional Properties of Utomilumab and Urelumab." Nature Communications, vol. 9, no. 1, 2018, p. 4679.
Chin SM, Kimberlin CR, Roe-Zurz Z, et al. Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab. Nat Commun. 2018;9(1):4679.
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. (2018). Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab. Nature Communications, 9(1), 4679. https://doi.org/10.1038/s41467-018-07136-7
Chin SM, et al. Structure of the 4-1BB/4-1BBL Complex and Distinct Binding and Functional Properties of Utomilumab and Urelumab. Nat Commun. 2018 11 8;9(1):4679. PubMed PMID: 30410017.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab. AU - Chin,S Michael, AU - Kimberlin,Christopher R, AU - Roe-Zurz,Zygy, AU - Zhang,Pamela, AU - Xu,Allison, AU - Liao-Chan,Sindy, AU - Sen,Debasish, AU - Nager,Andrew R, AU - Oakdale,Nicole Schirle, AU - Brown,Colleen, AU - Wang,Feng, AU - Yang,Yuting, AU - Lindquist,Kevin, AU - Yeung,Yik Andy, AU - Salek-Ardakani,Shahram, AU - Chaparro-Riggers,Javier, Y1 - 2018/11/08/ PY - 2018/03/30/received PY - 2018/10/09/accepted PY - 2018/11/10/entrez PY - 2018/11/10/pubmed PY - 2019/5/6/medline SP - 4679 EP - 4679 JF - Nature communications JO - Nat Commun VL - 9 IS - 1 N2 - 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/30410017/Structure_of_the_4_1BB/4_1BBL_complex_and_distinct_binding_and_functional_properties_of_utomilumab_and_urelumab_ L2 - https://doi.org/10.1038/s41467-018-07136-7 DB - PRIME DP - Unbound Medicine ER -