Top ▲

4-1BB

Click here for help

Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1878

Nomenclature: 4-1BB

Systematic Nomenclature: TNFRSF9

Family: Tumour necrosis factor (TNF) receptor family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 255 1p36.23 TNFRSF9 TNF receptor superfamily member 9
Mouse 1 256 4 81.52 cM Tnfrsf9 tumor necrosis factor receptor superfamily, member 9
Rat 1 308 9 Tnfrsf9 TNF receptor superfamily member 9
Previous and Unofficial Names Click here for help
ILA | CD137 | Ly63 | tumor necrosis factor receptor superfamily, member 9 | tumor necrosis factor receptor superfamily
Database Links Click here for help
Alphafold
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands Click here for help
4-1BB ligand {Sp: Human}
Adaptor proteins (Human)
TRAF1, TRAF2, TRAF3

Download all structure-activity data for this target as a CSV file go icon to follow link

Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
utomilumab Peptide Primary target of this compound Immunopharmacology Ligand Hs Agonist 8.1 pKd 3
pKd 8.1 (Kd 8.7x10-9 M) [3]
Description: Binding to 4-1BB extracellular domain measured using a surface plasmon resonance (SPR) biosensor assay.
urelumab Peptide Primary target of this compound Immunopharmacology Ligand Hs Agonist 7.8 pKd 4
pKd 7.8 (Kd 1.661x10-8 M) [4]
Description: Dissociation constant for the 20H4-9-IgG4 clone binding to human 4-1BB
Antibody Comments
Pfizer are developing utomilumab (PF-05082566) as a novel immuno-oncology biologic.
Bristol Meyers Squibb are developing urelumab (BMS-663513) for its potential immunostimulatory and antineoplastic activities.
Alligator Bioscience have their agonistic anti-4-1BB monoclonal, ATOR-1017 in preclinical development. ATOR-1017 is likely the subject of patent WO2018091740A2 [1]. It is an IgG4 antibody with enhanced ability to cross-link to Fc-γ receptors on immune cells, and therefore has a high tumour killing capacity.
Immunopharmacology Comments
4-1BB is a costimulatory receptor that is highly expressed on both T cells and NK cells in the tumour environment. Since activation of 4-1BB produces an immunostimulatory effect that supports the immune cells involved in tumour control it is a target for immuno-oncology drug development [5]. Targeting 4-1BB using monoclonal antibodies that act as agonists produces an immunostimulatory effect that enhances T-cell function and promotes anti-tumour activity [3]. For example, agonist antibody utomilumab is reported to enhance T cell function and promote anti-tumour action in cancer xenograft models [3], and both utomilumab and urelumab have advanced to clinical trial. Merus and Incyte are co-developing a 4-1BB/PD-L1 bispecific named MCLA-145 that has progressed to Phase 1 trial in patients with advanced or recurrent/metastatic solid tumours (see NCT03922204). The benefit of engaging both of these targets is that MCLA-145 simulatneously activates immune effector cells (4-1BB driven) and blocks inhibitory signals (PD-L1 driven) in these same cells, within the tumour microenvironment, thereby propagating a two pronged attack on the cancer cells. Compass Therapeutics' CTX-471 (a fully human anti-4-1BB antibody [2]) has begun Phase 1 evaluation as a monotherapy in patients with locally advanced and metastatic solid tumours whose cancers have progressed on anti-PD-1/anti-PD-L1 therapies (see NCT03881488).
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0033209 tumor necrosis factor-mediated signaling pathway TAS
General Comments
4-1BB (CD137, TNFRSF9) is a costimulatory receptor expressed on T cells, ligand activation of which under normal circumstances stimulates cellular proliferation, survival, and cytokine production.

References

Show »

1. Ellmark P, Fritzell S, Furebring C, Petersson J, Säll A, Smith KE, Varas L, Von SL, Veitonmäki N. (2018) Novel antibodies and uses thereof. Patent number: WO2018091740A2. Assignee: Alligator Bioscience Ab. Priority date: 21/11/2016. Publication date: 24/05/2018.

2. Eskiocak U, Guzman W, Wolf B, Cummings C, Milling L, Wu HJ, Ophir M, Lambden C, Bakhru P, Gilmore DC et al.. (2020) Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity. JCI Insight, 5 (5): e133647. DOI: 10.1172/jci.insight.133647 [PMID:32161196]

3. Fisher TS, Kamperschroer C, Oliphant T, Love VA, Lira PD, Doyonnas R, Bergqvist S, Baxi SM, Rohner A, Shen AC et al.. (2012) Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol Immunother, 61 (10): 1721-33. [PMID:22406983]

4. Jure-Kunkel, M, Hefta LJ, Santoro M, Ganguly S, Halk EL. (2005) Fully human antibodies against human 4-1bb (cd137). Patent number: WO2005035584. Assignee: Bristol-Myers Squibb Company. Priority date: 10/10/2003. Publication date: 21/04/2005.

5. Makkouk A, Chester C, Kohrt HE. (2016) Rationale for anti-CD137 cancer immunotherapy. Eur J Cancer, 54: 112-119. [PMID:26751393]

Contributors

Show »

How to cite this page