4-1BB and 4-1BBL Pathway

4-1BB and 4-1BBL Pathway

4-1BB, also well-known as CD137 and TNFRSF9, is an inducible costimulatory protein from the tumor necrosis factor (TNF) superfamily best known for enhancing CD8+ T cell proliferation and survival in a CD28-independent manner. Its ligand, 4-1BBL (CD137L or TNFSF9), is mainly expressed on myeloid cells. Similar to other members of the TNF superfamily, 4-1BB signaling is bidirectional. Thus, ligation influences the function of ligand-bearing cells and those expressing the receptor. 4-1BB signaling preferentially expands CD8+ T cells and induces Th1 responses. Its reverse signaling, via 4-1BBL, amplifies the innate immune responses by enhancing monocyte proliferation, migration, and maturation into Th1-inducing DCs and augmenting cytokine production by peritoneal macrophages.

Multimerization of 4-1BB by natural ligand and agonist mAbs. Fig.1 Multimerization of 4-1BB by natural ligand and agonist mAbs. (Melero, 2008)

Targeting 4-1BB in Immuno-Oncology

4-1BB and 4-1BBL pathway has been well characterized in the process of hematopoiesis, inflammation, and immune tolerance. The dual ability of 4-1BB to stimulate strong effector T cell responses toward pathogens while restricting autoimmune disease has made this receptor an attractive target for cancer immunotherapy. Although agonist antibodies have been the best-studied modality for activating 4-1BB, the immune pathologies associated with their use have prompted the development of alternate therapeutics. Promising 4-1BB targeted therapies include agonist antibodies, soluble 4-1BBL, and aptamers. Clinical trials of two leading agonist antibodies are ongoing in multiple cancer indications, and both antibodies demonstrate distinct activities in the clinic.

Table 1 Murine antitumor models targeted the 4-1BB and 4-1BBL pathway. (Cheuk, 2004)

Murine antitumor models targeted the 4-1BB and 4-1BBL pathway.

Combinational Therapies targeting 4-1BB

The addition of 4-1BB agonists to other therapeutic modalities could potentiate more robust antitumor responses while necessitating reduced dosing, therefore limiting the severity of 4-1BB associated adverse events. So far, many studies have shown cooperative and synergistic therapeutic benefits by combining 4-1BB agonists with different antitumor therapies. The most alluring combinations are those that combine 4-1BB agonists with T cell immune checkpoint blockade.

  • Combining anti-4-1BB with gene therapy and oncolytic virotherapy
  • Combining 4-1BB agonists with CTLA-4 blockade
  • Combining 4-1BB agonists with radiation therapy
  • Combining 4-1BB activation with chemotherapy
  • Combining 4-1BB agonists with TNF receptor agonists
  • Targeting 4-1BB and the PD-1/PD-L1 axis to elicit potent antitumor effects
  • ……

Creative Biolabs has successfully delivered services for many projects in 4-1BB and 4-1BBL molecules research. We offer a comprehensive set of services for clients to support your immune checkpoint research, including Immune Checkpoint Antibody Development, Immune Checkpoint Targeted Small Molecule Drug Development, and Immune Checkpoint Assays. Please contact us for detailed information and deeper communication to learn how we can be involved in your projects.


  1. Melero, I.; et al. Multi-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies. Trends in pharmacological sciences. 2008, 29(8): 383-390.
  2. Cheuk, A. T. C.; et al. Role of 4-1BB: 4-1BB ligand in cancer immunotherapy. Cancer gene therapy. 2004, 11(3): 215-226.

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