Target Information

Target General Information

Target ID

T93923 (Former ID: TTDNC00406)

Target Name

Co-stimulatory molecule 4-1BB (CD137)

Synonyms

Tumor necrosis factor receptor superfamily member 9; T-cell antigen ILA; T-cell antigen 4-1BB homolog; ILA; CDw137; 4-1BB ligand receptor

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Gene Name

TNFRSF9

Target Type

Clinical trial target

[1]

Disease

[+] 8 Target-related Diseases

Melanoma [ICD-11: 2C30]

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

Acute myeloid leukaemia [ICD-11: 2A60]

B-cell lymphoma [ICD-11: 2A86]

Malignant haematopoietic neoplasm [ICD-11: 2B33]

Non-small-cell lung cancer [ICD-11: 2C25]

Lymphoma [ICD-11: 2A80-2A86]

Mature B-cell lymphoma [ICD-11: 2A85]

Function

Possibly active during T cell activation. Receptor for TNFSF9/4-1BBL.

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BioChemical Class

Cytokine receptor

UniProt ID

TNR9_HUMAN

Sequence

MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQR
TCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDC
CFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPARE
PGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDG
CSCRFPEEEEGGCEL

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3D Structure

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AlphaFold

HIT2.0 ID

T72U9G

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 6 Clinical Trial Drugs

Anti-CD137

Drug Info

Phase 2

Solid tumour/cancer

[2]

Urelumab

Drug Info

Phase 2

Solid tumour/cancer

[3], [4]

CD137 CAR-T Cell

Drug Info

Phase 1/2

Acute lymphoblastic leukaemia

[7]

MG7-CART

Drug Info

Phase 1/2

Acute myeloid leukaemia

[8]

CD28 and CD137 CAR-T Cells

Drug Info

Phase 1

Acute lymphoblastic leukaemia

[20]

PF-05082566

Drug Info

Phase 1

Non-hodgkin lymphoma

[21]

Mode of Action

[+] 4 Modes of Action

Agonist

[+] 1 Agonist drugs

Urelumab

Drug Info

[3]

CAR-T-Cell-Therapy

[+] 2 CAR-T-Cell-Therapy drugs

CD137 CAR-T Cell

Drug Info

[7]

MG7-CART

Drug Info

[8]

CAR-T-Cell-Therapy(Dual specific)

[+] 1 CAR-T-Cell-Therapy(Dual specific) drugs

CD28 and CD137 CAR-T Cells

Drug Info

[20]

Modulator

[+] 2 Modulator drugs

PF-05082566

Drug Info

[22]

HG-1051

Drug Info

[1]

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)		30.168 (54/179)	2.06E-10

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	4	Degree centrality	4.30E-04	Betweenness centrality	1.67E-05
Closeness centrality	2.04E-01	Radiality	1.36E+01	Clustering coefficient	1.67E-01
Neighborhood connectivity	3.03E+01	Topological coefficient	3.04E-01	Eccentricity	11
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 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

WikiPathways

[+] 1 WikiPathways

TCR Signaling Pathway

References

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REF 1

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1878).

REF 2

ClinicalTrials.gov (NCT00612664) Phase II, 2nd Line Melanoma - RAND Monotherapy. 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 (NCT04775680) Study of ADG106 In Combination With PD-1 Antibody In Advanced or Metastatic Solid Tumors and/or Non Hodgkin Lymphoma. U.S. National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT04442126) A Study of NM21-1480 in Adult Patients With Advanced Solid Tumors. U.S. National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT02965092) CD19 Chimeric Antigen Receptor (CAR)-Modified T Cell Therapy in Treating Patients With B-cell Malignancies

REF 8

ClinicalTrials.gov (NCT02862704) A Study of MG7 Redirected Autologous T Cells for Advanced MG7 Positive Liver Metastases(MG7-CART)

REF 9

ClinicalTrials.gov (NCT04049903) Study to Investigate the Safety, Blood Levels and Activity of MP0310 (AMG 506) in Patients With Advanced Solid Tumors. U.S. National Institutes of Health.

REF 10

ClinicalTrials.gov (NCT03922204) A Study of Bispecific Antibody MCLA-145 in Patients With Advanced or Metastatic Malignancies. U.S. National Institutes of Health.

REF 11

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

REF 12

ClinicalTrials.gov (NCT01307267) A Study Of PF-05082566 As A Single Agent And In Combination With Rituximab. U.S. National Institutes of Health.

REF 13

ClinicalTrials.gov (NCT04130542) Phase 1 Trial of LVGN6051 as Single Agent and in Combination With Keytruda (MK-3475-A31/KEYNOTE-A31) in Advanced or Metastatic Malignancy. U.S. National Institutes of Health.

REF 14

ClinicalTrials.gov (NCT04121676) Anti-CD137 Monoclonal Antibody in Patients With Advanced Cancer. U.S. National Institutes of Health.

REF 15

ClinicalTrials.gov (NCT03881488) Study of CTX-471 in Patients Post PD-1/PD-L1 Inhibitors in Metastatic or Locally Advanced Malignancies. U.S. National Institutes of Health.

REF 16

ClinicalTrials.gov (NCT04083599) GEN1042 Safety Trial in Subjects With Malignant Solid Tumors. U.S. National Institutes of Health.

REF 17

ClinicalTrials.gov (NCT03917381) GEN1046 Safety Trial in Patients With Malignant Solid Tumors. U.S. National Institutes of Health.

REF 18

ClinicalTrials.gov (NCT03809624) Study of INBRX-105 in Patients With Solid Tumors (PDL1x41BB). U.S. National Institutes of Health.

REF 19

Clinical pipeline report, company report or official report of Roche

REF 20

ClinicalTrials.gov (NCT02186860) Chimeric Antigen Receptor (CAR)-Modified T Cell Therapy in Treating Patients With Acute Lymphoblastic Leukemia

REF 21

ClinicalTrials.gov (NCT02179918) A Study Of 4-1BB Agonist PF-05082566 Plus PD-1 Inhibitor MK-3475 In Patients With Solid Tumors (B1641003/KEYNOTE-0036). U.S. National Institutes of Health.

REF 22

Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol Immunother. 2012 Oct;61(10):1721-33.

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