Target Information

Target General Information

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Target ID

T15000 (Former ID: TTDC00259)

Target Name

Cytotoxic T-lymphocyte protein 4 (CTLA-4)

Synonyms

Cytotoxic T-lymphocyte-associated antigen 4; CTLA-4; CD152

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Gene Name

CTLA4

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Liver cancer [ICD-11: 2C12]

Melanoma [ICD-11: 2C30]

Function

Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.

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BioChemical Class

Immunoglobulin

UniProt ID

CTLA4_HUMAN

Sequence

MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFVCEY
ASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLR
AMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDFLLWILAAVSSGLFFYSFL
LTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN

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3D Structure

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AlphaFold

HIT2.0 ID

T75U40

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Ipilimumab

Drug Info

Approved

Melanoma

[1], [2], [3]

Tremelimumab

Drug Info

Approved

Hepatocellular carcinoma

[4]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

AGEN1884

Drug Info

Phase 1/2

Cervical cancer

[13]

TRemelimumab + MEDI0562

Drug Info

Phase 1

Solid tumour/cancer

[25]

Mode of Action

[+] 4 Modes of Action

Modulator

[+] 3 Modulator drugs

Tremelimumab

Drug Info

[26]

Concatameric CTLA4Ig

Drug Info

[26]

CTLA-4-XTEN

Drug Info

[26]

Antagonist

[+] 1 Antagonist drugs

AGEN1884

Drug Info

[13], [25]

Agonist

[+] 1 Agonist drugs

TRemelimumab + MEDI0562

Drug Info

[25]

Inhibitor

[+] 2 Inhibitor drugs

Alpha-D-Mannose

Drug Info

[27]

Fucose

Drug Info

[27]

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
T-cell-specific surface glycoprotein CD28 (CD28)	PF15910	31.250 (60/192)	1.97E-13

KEGG Pathway	Pathway ID	Affiliated Target
Cell adhesion molecules	hsa04514	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
T cell receptor signaling pathway	hsa04660	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	15	Degree centrality	1.61E-03	Betweenness centrality	5.19E-04
Closeness centrality	2.28E-01	Radiality	1.40E+01	Clustering coefficient	1.33E-01
Neighborhood connectivity	3.35E+01	Topological coefficient	1.06E-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

[+] 4 KEGG Pathways

Cell adhesion molecules (CAMs)

T cell receptor signaling pathway

Autoimmune thyroid disease

Rheumatoid arthritis

PID Pathway

[+] 1 PID Pathways

Calcineurin-regulated NFAT-dependent transcription in lymphocytes

Reactome

[+] 1 Reactome Pathways

CTLA4 inhibitory signaling

WikiPathways

[+] 4 WikiPathways

Vitamin D Receptor Pathway

T-Cell Receptor and Co-stimulatory Signaling

Allograft Rejection

Costimulation by the CD28 family

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.

REF 2

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. (Ligand id: 6888).

REF 3

2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.

REF 4

FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 761289.

REF 5

ClinicalTrials.gov (NCT04474119) KN046 in Subjects With Advanced Squamous Non-small Cell Lung Cancer. U.S. National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT00308867) Photodynamic Therapy With PD P 506 A or Its Placebo Compared With Cryosurgery for the Treatment of Mild to Moderate Actinic Keratosis. U.S.National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT04380805) A Study of AK104, a PD-1/CTLA-4 Bispecific Antibody in Subjects With Recurrent/Metastatic Cervical Cancer. U.S. National Institutes of Health.

REF 8

ClinicalTrials.gov (NCT05848011) A Phase 2, Randomized, Open-Label, Study of Lorigerlimab With Docetaxel or Docetaxel Alone in Participants With Metastatic Castration-Resistant Prostate Cancer. U.S.National Institutes of Health.

REF 9

ClinicalTrials.gov (NCT05005728) Phase 2 Multiple-Dose, Multiple-Arm, Parallel Assignment Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of XmAb?20717 Alone or in Combination With Chemotherapy or Targeted Therapies in Selected Subjects With Metastatic Castration-Resistant Prostate Cancer. U.S.National Institutes of Health.

REF 10

ClinicalTrials.gov (NCT03994601) An Investigational Immunotherapy Study of BMS-986288 Alone and in Combination With Nivolumab in Advanced Solid Cancers. U.S. National Institutes of Health.

REF 11

ClinicalTrials.gov (NCT03179436) Study of Quavonlimab (MK-1308) in Combination With Pembrolizumab (MK-3475) in Advanced Solid Tumors (MK-1308-001). U.S. National Institutes of Health.

REF 12

ClinicalTrials.gov (NCT05033132) An Open-label, Multicenter Phase II Study Evaluating Balstilimab Alone or Balstilimab in Combination With Zalifrelimab in Patients With Advanced Cervical Cancer. U.S.National Institutes of Health.

REF 13

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

REF 14

ClinicalTrials.gov (NCT04501276) ADG116 in Patients With Advanced/Metastatic Solid Tumors. U.S. National Institutes of Health.

REF 15

ClinicalTrials.gov (NCT03860272) Fc-Engineered Anti-CTLA-4 Monoclonal Antibody in Advanced Cancer. U.S. National Institutes of Health.

REF 16

ClinicalTrials.gov (NCT04140526) Safety, PK and Efficacy of ONC-392 in Monotherapy and in Combination of Anti-PD-1 in Advanced Solid Tumors and NSCLC (PRESERVE-001). U.S. National Institutes of Health.

REF 17

ClinicalTrials.gov (NCT03849469) A Study of XmAb22841 Monotherapy & in Combination w/ Pembrolizumab in Subjects w/ Selected Advanced Solid Tumors (DUET-4). U.S. National Institutes of Health.

REF 18

ClinicalTrials.gov (NCT04606472) A Study of SI-B003, a PD-1/CTLA-4 Bispecific Antibody, in Patients With Advanced Solid Tumors. U.S. National Institutes of Health.

REF 19

Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signaling Pathway.J Med Chem. 2019 Feb 28;62(4):1715-1730.

REF 20

ClinicalTrials.gov (NCT03530397) A Study to Evaluate MEDI5752 in Subjects With Advanced Solid Tumors. U.S. National Institutes of Health.

REF 21

ClinicalTrials.gov (NCT03761017) MGD019 DART Protein in Unresectable/Metastatic Cancer. U.S. National Institutes of Health.

REF 22

ClinicalTrials.gov (NCT04186637) An Open-label Study of ALPN-202 in Subjects With Advanced Malignancies (NEON-1). U.S. National Institutes of Health.

REF 23

ClinicalTrials.gov (NCT04699929) A Open-Label, Phase I Dose Escalation Study to Evaluate the Safety, Tolerability,Efficacy and Pharmacokinetics of YH001 in Subjects With Advanced Solid Tumors. U.S.National Institutes of Health.

REF 24

Clinical pipeline report, company report or official report of Klus Pharma

REF 25

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

REF 26

REF 27

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

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