Target Information

Target General Information

Target ID

T15344 (Former ID: TTDI02197)

Target Name

Activation-inducible TNFR family receptor (TNFRSF18)

Synonyms

UNQ319/PRO364; Tumor necrosis factor receptor superfamily member 18; Glucocorticoid-induced TNFR-related protein; GITR; CD357; AITR

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Gene Name

TNFRSF18

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Melanoma [ICD-11: 2C30]

Metastatic lymph node neoplasm [ICD-11: 2D60]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

Seems to be involved in interactions between activated T-lymphocytes and endothelial cells and in the regulation of T-cell receptor-mediated cell death. Mediated NF-kappa-B activation via the TRAF2/NIK pathway. Receptor for TNFSF18.

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BioChemical Class

Cytokine receptor

UniProt ID

TNR18_HUMAN

Sequence

MAQHGAMGAFRALCGLALLCALSLGQRPTGGPGCGPGRLLLGTGTDARCCRVHTTRCCRD
YPGEECCSEWDCMCVQPEFHCGDPCCTTCRHHPCPPGQGVQSQGKFSFGFQCIDCASGTF
SGGHEGHCKPWTDCTQFGFLTVFPGNKTHNAVCVPGSPPAEPLGWLTVVLLAVAACVLLL
TSAQLGLHIWQLRSQCMWPRETQLLLEVPPSTEDARSCQFPEEERGERSAEEKGRLGDLW
V

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 8 Clinical Trial Drugs

INCAGN01876

Drug Info

Phase 2

Solid tumour/cancer

[2]

INCAGN1876

Drug Info

Phase 1/2

Solid tumour/cancer

[3], [4]

TRX-518

Drug Info

Phase 1/2

Solid tumour/cancer

[3], [4]

AMG 228

Drug Info

Phase 1

Solid tumour/cancer

[5]

ASP1951

Drug Info

Phase 1

Solid tumour/cancer

[6]

MK-4166

Drug Info

Phase 1

Solid tumour/cancer

[7]

REGN6569

Drug Info

Phase 1

Squamous head and neck cell carcinom

[8]

TRX518

Drug Info

Phase 1

Solid tumour/cancer

[9]

Mode of Action

[+] 2 Modes of Action

Agonist

[+] 4 Agonist drugs

INCAGN01876

Drug Info

[10]

INCAGN1876

Drug Info

[3]

AMG 228

Drug Info

[11]

ASP1951

Drug Info

[6]

Inhibitor

[+] 1 Inhibitor drugs

REGN6569

Drug Info

[13]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Activation-inducible TNFR family receptor (TNFRSF18)		100.000 (241/241)	5.54E-177
Co-stimulatory molecule 4-1BB (CD137)	PF00020	29.050 (52/179)	8.38E-09
OX40L receptor (CD134)	PF00020	38.710 (24/62)	3.12E-07
Osteoclast differentiation factor receptor (ODFR)	PF18278 ; PF00020	29.310 (34/116)	4.53E-06
Osteoclastogenesis inhibitory factor (TNFRSF11B)	PF00531 ; PF00020	33.766 (26/77)	1.45E-05
Tumor necrosis factor receptor superfamily member 6B (TNFRSF6B)	PF00020	37.879 (25/66)	1.48E-05
Death receptor 6 (CD358)	PF00531 ; PF00020	36.923 (24/65)	1.97E-05
CD40L receptor (CD40)	PF00020	27.966 (33/118)	5.00E-03
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KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Cytokine-cytokine receptor interaction	hsa04060	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	2.02E-04
Closeness centrality	1.92E-01	Radiality	1.33E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	1.00E+01	Topological coefficient	5.00E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Cytokine-cytokine receptor interaction

NetPath Pathway

[+] 1 NetPath Pathways

TCR Signaling Pathway

PID Pathway

[+] 2 PID Pathways

Downstream signaling in na&#xef

Reactome

[+] 1 Reactome Pathways

TNFs bind their physiological receptors

References

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REF 1

Immuno-oncology moves beyond PD-1. Nat Biotechnol. 2015 Jul;33(7):673-5.

REF 2

ClinicalTrials.gov (NCT03277352) INCAGN01876 in Combination With Immune Therapies in Subjects With Advanced or Metastatic Malignancies. U.S. National Institutes of Health.

REF 3

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 4

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 5

ClinicalTrials.gov (NCT02437916) Safety Study of AMG 228 to Treat Solid Tumors. U.S. National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT03799003) A Study of ASP1951 in Subjects With Advanced Solid Tumors. U.S. National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT02132754) Study of MK-4166 in Participants With Advanced Solid Tumors (MK-4166-001). U.S. National Institutes of Health.

REF 8

ClinicalTrials.gov (NCT04465487) Study of REGN6569 and Cemiplimab in Adult Patients With Advanced Solid Tumor Malignancies. U.S. National Institutes of Health.

REF 9

ClinicalTrials.gov (NCT02628574) Phase 1 Open-label Study of TRX518 Monotherapy and TRX518 in Combination With Gemcitabine, Pembrolizumab, or Nivolumab. U.S. National Institutes of Health.

REF 10

Clinical pipeline report, company report or official report of Agenus.

REF 11

Dose escalation results from a first-in-human, phase 1 study of glucocorticoid-induced TNF receptor-related protein agonist AMG 228 in patients with advanced solid tumors. J Immunother Cancer. 2018 Sep 25;6(1):93.

REF 12

Immuno-oncology moves beyond PD-1. Nat Biotechnol. 2015 Jul;33(7):673-5.

REF 13

Clinical pipeline report, company report or official report of Regeneron Pharmaceuticals.

REF 14

Clinical pipeline report, company report or official report of Leap Therapeutics.

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