cytotoxic T-lymphocyte-associated protein 4 (CD152) | Other immune checkpoint proteins | IUPHAR/BPS Guide to PHARMACOLOGY

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cytotoxic T-lymphocyte-associated protein 4 (CD152)

target has curated data in GtoImmuPdb

Target id: 2743

Nomenclature: cytotoxic T-lymphocyte-associated protein 4 (CD152)

Abbreviated Name: CTLA-4

Family: Other immune checkpoint proteins, CD molecules

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 223 2q33 CTLA4 cytotoxic T-lymphocyte associated protein 4
Mouse - 223 1 C Ctla4 cytotoxic T-lymphocyte-associated protein 4
Rat - 223 9q31 Ctla4 cytotoxic T-lymphocyte-associated protein 4
Previous and Unofficial Names
ICOS | cytotoxic T-lymphocyte-associated protein 4
Database Links
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
Comments: T cell-expressed CTLA-4 binds the costimulatory molecules CD80 (Kd 208 nM) and CD86 (Kd 2000 nM) on antigen presenting cells [6]. These binding affiities were measured using surface plasmon resonance, using immobilised CD80 or CD86 and monomeric CTLA-4 in the mobile phase, but the endogenous interactions are modulated by receptor (CD80 and CD86) oligomerisation and ligand (CTLA-4) dimerisation [6].

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Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
ipilimumab Hs Binding >9.0 pKd 7
pKd >9.0 (Kd <1x10-9 M) [7]
tremelimumab Hs Binding 8.9 pKd 8
pKd 8.9 (Kd 1.24x10-9 M) [8]
Description: Average Kd from associated patent, for a competition ELISA assessing binding of the antibody to CTLA4.
Antibody Comments
Agenus have a next-generation, Fc-engineered antagonistic anti-CTLA-4 monoclonal, coded AGEN1181, in their development pipeline. Modifications within the Fc region of the antibody (which interacts with Fcγ receptors on other immune cells, such as antigen-presenting cells) were included to enhance antitumour immunity [14]. As of April 2019 AGEN1181 is beginning Phase 1 evaluation in subjects with advanced solid tumours (see NCT03860272).
Immunopharmacology Comments
CTLA-4 is expressed almost exclusively on CD4+ and CD8+ T cells. It functions as an immune checkpoint providing an inhibitory signal as a balance to stimulatory signals of the immune response i.e. it plays a crucial role in the maintenance of T cell homeostasis [11]. It binds to CD80/86 on antigen-presenting cells and blocks co-stimulation of both the T cells and AP cells. The discovery that CTLA-4 retains its biological activity in soluble form paved the way for the development of CTLA-4 fusion proteins which now have proven efficacy as therapeutics in autoimmune diseases and organ rejection.

The approved drugs abatacept (1st generation) and belatacept (2nd generation) are CTLA-4-Ig fusion proteins that are approved for clinical indications (rheumatoid and psoriatic arthritis and prophylaxis of organ rejection respectively), but their use, and in particular their route of adminisatration (predominantly i.v.), is limited by their molecular stability and pharmacokinetics. To overcome such limitations CTLA-4 fusion proteins with optimised affinity, selectivity, stability, FcRn binding, and superior in vivo efficacy are being developed [2,5,12].
Immuno Process Associations
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 6 GO processes
GO:0031295 T cell costimulation TAS
GO:0045589 regulation of regulatory T cell differentiation TAS
GO:0045590 negative regulation of regulatory T cell differentiation IDA
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
GO:0042129 regulation of T cell proliferation IEA
GO:0042130 negative regulation of T cell proliferation IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0030889 negative regulation of B cell proliferation IMP
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 9 GO processes
GO:0030889 negative regulation of B cell proliferation IMP
GO:0031295 T cell costimulation TAS
GO:0045589 regulation of regulatory T cell differentiation TAS
GO:0045590 negative regulation of regulatory T cell differentiation IDA
GO:0050852 T cell receptor signaling pathway IBA
GO:0050853 B cell receptor signaling pathway IMP
click arrow to show/hide IEA associations
GO:0042129 regulation of T cell proliferation IEA
GO:0042130 negative regulation of T cell proliferation IEA
GO:0050777 negative regulation of immune response IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 2 GO processes
GO:0045589 regulation of regulatory T cell differentiation TAS
GO:0045590 negative regulation of regulatory T cell differentiation IDA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 3 GO processes
GO:0031295 T cell costimulation TAS
GO:0045590 negative regulation of regulatory T cell differentiation IDA
click arrow to show/hide IEA associations
GO:0042130 negative regulation of T cell proliferation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 8 GO processes
GO:0030889 negative regulation of B cell proliferation IMP
GO:0031295 T cell costimulation TAS
GO:0045589 regulation of regulatory T cell differentiation TAS
GO:0045590 negative regulation of regulatory T cell differentiation IDA
GO:0050852 T cell receptor signaling pathway IBA
GO:0050853 B cell receptor signaling pathway IMP
click arrow to show/hide IEA associations
GO:0042129 regulation of T cell proliferation IEA
GO:0042130 negative regulation of T cell proliferation IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Autoimmune lymphoproliferative syndrome, type V; ALPS5
Synonyms: Autoimmune lymphoproliferative syndrome [Disease Ontology: DOID:6688]
CTLA4 haploinsuffiency with autoimmune infiltration; CHAI [OMIM: 616100]
Disease Ontology: DOID:6688
OMIM: 616100
Disease:  Celiac disease, susceptibility to, 3; CELIAC3
Synonyms: Celiac disease [Orphanet: ORPHA555] [Disease Ontology: DOID:10608]
Gluten-sensitive enteropathy, susceptibility to, 3 [OMIM: 609755]
Disease Ontology: DOID:10608
OMIM: 609755
Orphanet: ORPHA555
Disease:  Diabetes mellitus, insulin-dependent, 12; IDDM12
Synonyms: Insulin-dependent diabetes mellitus 12 [OMIM: 601388]
type 1 diabetes mellitus [Disease Ontology: DOID:9744]
Disease Ontology: DOID:9744
OMIM: 601388
Disease:  Hashimoto thyroiditis
Synonyms: Autoimmune thyroiditis [Disease Ontology: DOID:7188]
Hashimoto struma [Orphanet: ORPHA855]
Disease Ontology: DOID:7188
OMIM: 140300
Orphanet: ORPHA855
Disease:  Systemic lupus erythematosus
Description: SLE is a complex autoimmune disease that is characterised by inflammation of various connective tissues, and symptoms include dermatitis, arthritis, inflammation of the kidneys (glomerulonephritis), vasculitis, inflammation of the tissue surrounding the heart, and seizures. It is caused by the production of autoantibodies against widely expressed nuclear, cytoplasmic, and cell surface molecules. Extracellular RNA in the circulation in combination with the presence of autoantibodies potently stimulates interferon production and immune system activation.
Disease Ontology: DOID:9074
OMIM: 152700
Orphanet: ORPHA536
Gene Expression and Pathophysiology Comments
Verma et al. (2017) provide a review of the role of CTLA-4 mutations in immune deficiency and autoimmune diseases, and discuss how understanding the normal biology of this protein is helping to direct rational therapeutic development [13].
Patients with immune dysregulation caused by defective expression of the LRBA gene (Uniprot P50851) have a reduced level of CTLA-4 protein. Their symptoms are responsive to abatacept CTLA-4 'replacement' therapy [10]. Identification of LRBA mutations underlying common variable immunodeficiency with autoimmunity (CVID8) is reported in [3], [4] and [10]. Alangari et al. (2012) [1] and Lo et al. (2015) [10] noted decreased CTLA-4 expression in these patients.
General Comments
CTLA-4 is genetically linked to and evolutionarily related to CD28 [9].
This protein contains an immunoglobulin (Ig)-like domain that resembles the antibody variable domain, that has been coined the 'V-set domain'. The genes for all human V-set domain containing proteins are listed in HGNC gene group 590.

References

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1. Alangari A, Alsultan A, Adly N, Massaad MJ, Kiani IS, Aljebreen A, Raddaoui E, Almomen AK, Al-Muhsen S, Geha RS et al.. (2012) LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J. Allergy Clin. Immunol., 130 (2): 481-8.e2. [PMID:22721650]

2. Bernett MJ, Chu SY, Leung I, Moore GL, Lee SH, Pong E, Chen H, Phung S, Muchhal US, Horton HM et al.. (2013) Immune suppression in cynomolgus monkeys by XPro9523: an improved CTLA4-Ig fusion with enhanced binding to CD80, CD86 and neonatal Fc receptor FcRn. MAbs, 5 (3): 384-96. [PMID:23549103]

3. Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, Kumararatne D, Doffinger R, Thrasher AJ, Nejentsev S. (2012) LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J. Allergy Clin. Immunol., 130 (6): 1428-32. [PMID:22981790]

4. Charbonnier LM, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, Massaad MJ, Garcia-Lloret M, Hanna-Wakim R, Dbaibo G et al.. (2015) Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J. Allergy Clin. Immunol., 135 (1): 217-27. [PMID:25468195]

5. Douthwaite J, Moisan J, Privezentzev C, Soskic B, Sabbah S, Cohen S, Collinson A, England E, Huntington C, Kemp B et al.. (2017) A CD80-Biased CTLA4-Ig Fusion Protein with Superior In Vivo Efficacy by Simultaneous Engineering of Affinity, Selectivity, Stability, and FcRn Binding. J. Immunol., 198 (1): 528-537. [PMID:27881707]

6. Greene JL, Leytze GM, Emswiler J, Peach R, Bajorath J, Cosand W, Linsley PS. (1996) Covalent dimerization of CD28/CTLA-4 and oligomerization of CD80/CD86 regulate T cell costimulatory interactions. J. Biol. Chem., 271 (43): 26762-71. [PMID:8900156]

7. Halk EL, Korman AJ, Lonberg N. (2001) Human ctla-4 antibodies and their uses. Patent number: WO2001014424. Assignee: Medarex Inc. Priority date: 24/08/1999. Publication date: 01/03/2001.

8. Hanson DC, Neveu MJ, Mueller EE, Hanke JH, Gilman SC, Davis CG, Corvalan JR. (2004) Human monoclonal antibodies to CTLA-4. Patent number: US6682736 B1. Assignee: Abgenix, Inc., Pfizer Inc.. Priority date: 22/12/1998. Publication date: 27/01/2004.

9. Linsley PS, Ledbetter JA. (1993) The role of the CD28 receptor during T cell responses to antigen. Annu. Rev. Immunol., 11: 191-212. [PMID:8386518]

10. Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, Zhang Y, Liu Z, Fritz JM, Marsh R et al.. (2015) AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science, 349 (6246): 436-40. [PMID:26206937]

11. McCoy KD, Le Gros G. (1999) The role of CTLA-4 in the regulation of T cell immune responses. Immunol. Cell Biol., 77 (1): 1-10. [PMID:10101680]

12. Oshima S, Fujii Y, Karrer EE, Takamura F, Chapin SJ, Neighbors M, Viswanathan S, Devens BH, Higashi Y, Mizuhara H. (2016) Immunosuppressive effect of ASP2408, a novel CD86-selective variant of CTLA4-Ig, in rats and cynomolgus monkeys. Int. Immunopharmacol., 40: 310-317. [PMID:27662596]

13. Verma N, Burns SO, Walker LSK, Sansom DM. (2017) Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin. Exp. Immunol., 190 (1): 1-7. [PMID:28600865]

14. Waight JD, Chand D, Dietrich S, Gombos R, Horn T, Gonzalez AM, Manrique M, Swiech L, Morin B, Brittsan C et al.. (2018) Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens. Cancer Cell, 33 (6): 1033-1047.e5. [PMID:29894690]

How to cite this page

Other immune checkpoint proteins: cytotoxic T-lymphocyte-associated protein 4 (CD152). Last modified on 07/08/2019. Accessed on 23/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2743.