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target has curated data in GtoImmuPdb
Target id: 1878
Nomenclature: 4-1BB
Systematic Nomenclature: TNFRSF9
Gene and Protein Information  |
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| 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 |
| ILA | CD137 | Ly63 | tumor necrosis factor receptor superfamily, member 9 | tumor necrosis factor receptor superfamily |
| Database Links |
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| Alphafold | Q07011 (Hs), P20334 (Mm) |
| ChEMBL Target | CHEMBL3712857 (Hs) |
| Ensembl Gene | ENSG00000049249 (Hs), ENSMUSG00000028965 (Mm), ENSRNOG00000036942 (Rn) |
| Entrez Gene | 3604 (Hs), 21942 (Mm), 500590 (Rn) |
| Human Protein Atlas | ENSG00000049249 (Hs) |
| KEGG Gene | hsa:3604 (Hs), mmu:21942 (Mm), rno:500590 (Rn) |
| OMIM | 602250 (Hs) |
| Pharos | Q07011 (Hs) |
| RefSeq Nucleotide | NM_003811 (Hs), NM_009404 (Mm), NM_181384 (Rn) |
| RefSeq Protein | NP_003802 (Hs), NP_033430 (Mm), NP_852049 (Rn) |
| UniProtKB | Q07011 (Hs), P20334 (Mm) |
| Wikipedia | TNFRSF9 (Hs) |
| 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 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
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| 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. |
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| 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 | ||
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| 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. |
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]
6. Upadhyaya P, Kristensson J, Lahdenranta J, Repash E, Ma J, Kublin J, Mudd GE, Luus L, Jeffrey P, Hurov K et al.. (2022) Discovery and Optimization of a Synthetic Class of Nectin-4-Targeted CD137 Agonists for Immuno-oncology. J Med Chem, 65 (14): 9858-9872. [PMID:35819182]
