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)

[+] 22 Clinical Trial Drugs

AK04

Drug Info

Phase 3

Actinic keratosis

[5]

KN046

Drug Info

Phase 3

Non-small-cell lung cancer

[6]

AK104

Drug Info

Phase 2

Cervical cancer

[7]

Lorigerlimab

Drug Info

Phase 2

Prostate cancer

[8]

Vudalimab

Drug Info

Phase 2

Prostate cancer

[9]

AGEN1884

Drug Info

Phase 1/2

Cervical cancer

[10]

BMS-986288

Drug Info

Phase 1/2

Solid tumour/cancer

[11]

MK-1308

Drug Info

Phase 1/2

Solid tumour/cancer

[12]

Zalifrelimab

Drug Info

Phase 1/2

Cervical cancer

[13]

A337

Drug Info

Phase 1

Aggressive cancer

[14]

ADG116

Drug Info

Phase 1

Solid tumour/cancer

[15]

AGEN1181

Drug Info

Phase 1

Solid tumour/cancer

[16]

ALPN-202

Drug Info

Phase 1

Solid tumour/cancer

[17]

BMS-986249

Drug Info

Phase 1

Solid tumour/cancer

[10]

MEDI5752

Drug Info

Phase 1

Solid tumour/cancer

[18]

MGD019

Drug Info

Phase 1

Solid tumour/cancer

[19]

ONC-392

Drug Info

Phase 1

Non-small-cell lung cancer

[20]

SI-B003

Drug Info

Phase 1

Solid tumour/cancer

[21]

TRemelimumab + MEDI0562

Drug Info

Phase 1

Solid tumour/cancer

[22]

XmAb20717

Drug Info

Phase 1

Solid tumour/cancer

[23]

XmAb22841

Drug Info

Phase 1

Solid tumour/cancer

[24]

YH001

Drug Info

Phase 1

Aggressive 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]

Inhibitor

[+] 12 Inhibitor drugs

KN046

Drug Info

[28]

AK104

Drug Info

[29]

BMS-986288

Drug Info

[32]

MK-1308

Drug Info

[33]

ADG116

Drug Info

[35]

AGEN1181

Drug Info

[36]

ALPN-202

Drug Info

[37]

MEDI5752

Drug Info

[38]

MGD019

Drug Info

[39]

ONC-392

Drug Info

[40]

Alpha-D-Mannose

Drug Info

[45]

Fucose

Drug Info

[45]

Antagonist

[+] 1 Antagonist drugs

AGEN1884

Drug Info

[10], [22]

Agonist

[+] 1 Agonist drugs

TRemelimumab + MEDI0562

Drug Info

[22]

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 (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 6

ClinicalTrials.gov (NCT04474119) KN046 in Subjects With Advanced Squamous Non-small Cell Lung Cancer. 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

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

REF 11

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 12

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 13

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 14

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

REF 15

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

REF 16

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

REF 17

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

REF 18

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

REF 19

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

REF 20

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 21

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 22

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

REF 23

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 24

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 25

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 26

REF 27

A multicenter, open-label phase Ib/II study of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) monotherapy in previously treated advanced non-small-cell lung cancer (AK104-202 study). Lung Cancer. 2023 Oct;184:107355.

REF 28

Clinical pipeline report, company report or official report of Alphamab Oncology.

REF 29

Clinical pipeline report, company report or official report of Akeso Biopharma.

REF 30

Clinical pipeline report, company report or official report of MacroGenics

REF 31

Clinical pipeline report, company report or official report of Xencor

REF 32

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

REF 33

Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer. Ann Oncol. 2021 Mar;32(3):395-403.

REF 34

Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study. J Clin Oncol. 2022 Mar 1;40(7):762-771.

REF 35

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

REF 36

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

REF 37

Clinical pipeline report, company report or official report of Alpine Immune Sciences.

REF 38

Bispecific Antibodies to PD-1 and CTLA4: Doubling Down on T Cells to Decouple Efficacy from Toxicity. Cancer Discov. 2021 May;11(5):1008-1010.

REF 39

Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule. Cell Rep Med. 2020 Dec 22;1(9):100163.

REF 40

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

REF 41

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

REF 42

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

REF 43

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

REF 44

Clinical pipeline report, company report or official report of Biocytogen

REF 45

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

REF 46

Therapeutic applications of aptamers. Expert Opin Investig Drugs. 2008 Jan;17(1):43-60.

REF 47

Clinical pipeline report, company report or official report of Biocytogen

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