Recombinant Human Fc-h4-1BBL Fusion Protein

The 4-1BB/4-1BBL immune checkpoint

The 4-1BB/4-1BBL axis plays an important role in immune regulation and is considered an immune checkpoint (IC). 

4-1BB (aka CD137 or TNFSF9) is a member of the TNFR (tumor necrosis factor receptor) superfamily. In humans, 4-1BB is expressed on a multitude of cells of the hematopoietic lineage. It is found on the surface of activated CD8+ and CD4+ T cells, including regulatory T cells (Tregs). Additionally, its expression can be induced on Natural Killer (NK) cells, B cells, monocytes, and  dendritic cells (DCs) upon activation [1,2].

4-1BBL (aka CD137L) is also a member of the TNFR family and is known as the sole ligand for 4-1BB. In humans, 4-1BBL is expressed in T cells, B cells, DCs and macrophages [1,2].

The interaction of 4-1BB on T cells with its ligand, 4-1BBL (CD137L), on antigen-presenting cells (APCs), triggers a TRAF1/TRAF2/NF‑κB‑dependent signaling which powerfully augments T-cell activation, proliferation, and survival [1]. This co-stimulatory axis also mediates the generation of memory T cells [1]

The 4-1BB/4-1BBL immune checkpoint in cancer

4-1BB expression in activated T cells has been an attractive target for cancer immunotherapy. Different strategies have been explored.
Two human agonistic monoclonal antibodies (mAbs) directed at 4-1BB, utomilumab (PF-05082566) and urelumab (BMS-663513), have entered phase I/II clinical trials. Whereas the IgG2 utomilumab is safe with relatively low efficacy, the IgG4 urelumab has a great antitumor efficacy but causes liver damage [2,3]. Utomilumab is being extensively tested in combination with IC inhibitory antibodies (e.g. Anti-CTLA-4 and Anti-PD-1) to treat different tumors, such as non-small cell lung cancer, kidney, head, and neck cancer [1,3]. Of note, agonistic 4-1BB mAbs may act on the depletion of Tregs through Fc-mediated effector functions [3]. A new generation of 4-1BB agonistic mAbs, other than utomilumab and urelumab, are being tested and are referenced in [2].
4-1BB-derived domains have been widely studied as costimulatory domains for genetically engineered T cells expressing chimeric antigen receptors (CART). The activation of the 4-1BB signaling in these CART cells promotes the formation of memory CART cells and long-term immune response against cancer cells [2,3].
4-1BB is expressed in various types of hematologic cancers and 4-1BBL in tumor cells, including carcinoma and colon cancers. However, the precise functions of 4-1BB/4-1BBL remain unclear in these malignancies [1, 2].

​References:

1. Bartkowiak, T. & Curran, M.A. 2015. 4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity. Front Oncol 5, 117.
2. Singh, R. et al., 2024. 4-1BB immunotherapy: advances and hurdles. Experimental & Molecular Medicine. 56(1):32-39.
3. Mascarelli, D.E, et al., 2021. Boosting Antitumor Response by Costimulatory Strategies Driven to 4-1BB and OX40 T-cell Receptors. Front. Cell Dev. Biol. 10.3389/fcell.2021.692982.