4-1BB | Tumour necrosis factor (TNF) receptor family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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4-1BB

  Target has curated data in GtoImmuPdb

Target id: 1878

Nomenclature: 4-1BB

Systematic Nomenclature: TNFRSF9

Family: Tumour necrosis factor (TNF) receptor family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 254 19p13.3 TNFRSF9 TNF receptor superfamily member 9
Mouse 1 309 17 D Tnfrsf9 tumor necrosis factor receptor superfamily, member 9
Rat 1 308 9 Tnfrsf9 TNF receptor superfamily member 9
Previous and Unofficial Names
ILA | CD137 | Ly63 | tumor necrosis factor receptor superfamily, member 9 | tumor necrosis factor receptor superfamily
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
4-1BB ligand {Sp: Human}
Adaptor proteins (Human)
TRAF1, TRAF2, TRAF3

Download all structure-activity data for this target as a CSV file

Antibodies
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Antibody Sp. Action Value Parameter Reference
utomilumab Hs Agonist 8.1 pKd 2
pKd 8.1 (Kd 8.7x10-9 M) [2]
Description: Binding to 4-1BB extracellular domain measured using a surface plasmon resonance (SPR) biosensor assay.
urelumab Hs Agonist 7.8 pKd 3
pKd 7.8 (Kd 1.661x10-8 M) [3]
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 [4]. Targeting 4-1BB using monoclonal antibodies that act as agonists produces an immunostimulatory effect that enhances T-cell function and promotes anti-tumour activity [2]. For example, agonist antibody utomilumab is reported to enhance T cell function and promote anti-tumour action in cancer xenograft models [2], 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.
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

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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. 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]

3. 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.

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

Contributors

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How to cite this page

David MacEwan.
Tumour necrosis factor (TNF) receptor family: 4-1BB. Last modified on 16/05/2019. Accessed on 21/07/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1878.