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

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.