4-1BB immunotherapy: advances and hurdles

Abstract

Since its initial description 35 years ago as an inducible molecule expressed in cytotoxic and helper T cells, 4-1BB has emerged as a crucial receptor in T-cell-mediated immune functions. Numerous studies have demonstrated the involvement of 4-1BB in infection and tumor immunity. However, the clinical development of 4-1BB agonist antibodies has been impeded by the occurrence of strong adverse events, notably hepatotoxicity, even though these antibodies have exhibited tremendous promise in in vivo tumor models. Efforts are currently underway to develop a new generation of agonist antibodies and recombinant proteins with modified effector functions that can harness the potent T-cell modulation properties of 4-1BB while mitigating adverse effects. In this review, we briefly examine the role of 4-1BB in T-cell biology, explore its clinical applications, and discuss future prospects in the field of 4-1BB agonist immunotherapy.

Fig. 1. This illustration depicts the cascade of events involved in 4-1BB signaling and its effects on T-cell function.

Upon interaction with 4-1BBL on antigen-presenting cells (APC), 4-1BB signaling begins by recruiting TRAF1 and TRAF2 to the TRAF-binding motif located in the cytoplasmic tail of 4-1BB, along with cIAP1 and cIAP2, forming the 4-1BB signaling complex. TRAF1 and TRAF2 lead to ERK1/2 activation through TRAF1 stimulation of ERK1/2 activity. The activation of ERK1/2 also induces the phosphorylation of the proapoptotic protein Bim. This phosphorylation event facilitates the proteasomal degradation of Bim, which, in turn, promotes T-cell survival. In the context of 4-1BB-induced NF-κB activation, the TRAF2-cIAP complex initiates the NF-κB pathway. The IKK complex comprises three subunits: two kinases, IKKα and IKKβ, along with the regulatory subunit NF-κB essential modulator (NEMO; also known as IKKγ). NF-κB induces the transcription of BCL-XL, BCL-2, and c-FLIP and stimulates the expression of IL-2, IL-4, and IFN-gamma, promoting the survival and cytotoxic activity of T cells. Additionally, TRAF2 recruitment fosters the activation of the JNK and p38 MAPK pathways. JNK translocates into the nucleus, where it interacts with the transcription factors JUN and ATF2, leading to the production of IL-2, IL-4, and IFN-gamma by T cells. TRAF TNF receptor-associated factor, cIAP cellular inhibitor of apoptosis protein, LUBAC linear ubiquitin chain assembly complex, NF-κB nuclear factor-κB, NEMO NF-κB essential modulator, IKK IκB kinase, JNK JUN N-terminal kinase.

Fig. 2. Representative structures of human and murine 4-1BB ligand‒receptor complexes.

a Human 4-1BB/4-1BBL complex (PDB ID: 6CPR): This complex illustrates the structure of a 4-1BB receptor and its ligand in both side view (left) and top view (right)^,. The 4-1BBL trimer is depicted in magenta, surrounded by three monomers of the 4-1BB receptor shown in blue. Notably, 4-1BBL binds to cysteine-rich domains (CRDs) 2 and 3 of the 4-1BB receptor. b Murine 4-1BB/4-1BBL complex (PDB ID: 6MKZ): This complex represents murine 4-1BBL in complex with its receptor 4-1BB, shown in side view (left) and top view (right)^,. A dimeric 4-1BB ligand (magenta) binds externally to two 4-1BB monomers (blue). Each murine 4-1BBL binds to CRD1, 2, and 3 of the murine 4-1BB monomer, with CRD2 being the primary interaction site. The RCSB PDB 3D Protein Feature View was employed to create these molecular representations. PDB, Protein Data Bank.

Fig. 3. Structural comparison of 4-1BB binding by utomilumab and urelumab.

a Utomilumab (heavy chain in green, light chain in magenta) binds alongside 4-1BB (blue), making contact at the junction between CRDs 3 and 4, thereby preventing the binding of 4-1BBL. This inhibition is likely due to steric occlusion (PDB ID: 6MI2)^,. b Urelumab (heavy chain in green, light chain in magenta) binds to the very N-terminus of the 4-1BB (blue) receptor on CRD-1, which is separate from the 4-1BBL binding site located on CRD-2 and CRD-3. Urelumab does not interfere with subsequent 4-1BBL binding to the 4-1BB receptor (PDB ID: 6MHR)^,. PDB, Protein Data Bank.