CD4 | CD molecules | IUPHAR Guide to IMMUNOPHARMACOLOGY

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CD4

  Target has curated data in GtoImmuPdb

Target id: 2995

Nomenclature: CD4

Family: 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 1 458 12p13.31 CD4 CD4 molecule
Mouse 1 457 6 F2; 6 59.17 cM Cd4 CD4 antigen
Rat 1 457 4q42 Cd4 Cd4 molecule
Gene and Protein Information Comments
Multiple alternatively spliced transcript variants encoding different isoforms have been identified in the human CD4 gene.
Previous and Unofficial Names
CD4 antigen (p55) | T-cell surface glycoprotein CD4 | cluster of differentiation 4
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
tregalizumab Hs Binding - - 11
[11]
ibalizumab Hs Binding - - 1
[1]
Immunopharmacology Comments
CD4 is being targeted for clinical utility in inflammatory diseases like rheumatoid arthritis (RA), neoplasms derived from T helper cells (T cell lymphomas and related malignancies), and for anti-HIV potential. Depending on the design of CD4 targeting antibodies, they can produce immunosuppressive effects via activation of Tregs and induction of tolerance, block HIV binding to CD4 to prevent HIV infection, or induce depletion of CD4+ T cells by apoptosis, ADCC, or CDC [6,10].

Rheumatoid arthritis
Zanolimumab (HuMax-CD4) is an anti-CD4 monoclonal (mAb) that was investigated for non-HIV indications. It has immunosuppressive activity that was expected to be of benefit in the treatment of chronic inflammatory conditions such as RA and psoriasis, and also for T cell lymphomas [5,8]. However, clinical trials evaluating zanolimumab have been terminated and development discontinued. Tregalizumab was a Phase 2 immunosuppresive anti-CD4 mAb for RA [3,7,11]. A combination of methotrexate plus tregalizumab failed to produce a better response than methotrexate alone in Phase 2 clinical trial (NCT01999192) [9].

HIV
The anti-CD4 mAb ibalizumab is non-immunosuppressive and acts as an HIV entry inhibitor [2,4]. It was FDA approved in March 2018 for the treatment of HIV patients who have limited conventional anti-retroviral treatment options.
Cell Type Associations
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
Immuno Cell Type:  T cells
Cell Ontology Term:   CD4-positive helper T cell (CL:0000492)
CD4-positive, alpha-beta T cell (CL:0000624)
CD4-positive, CD25-positive, alpha-beta regulatory T cell (CL:0000792)
CD4-positive, alpha-beta intraepithelial T cell (CL:0000793)
CD4-positive, alpha-beta cytotoxic T cell (CL:0000934)
effector CD4-positive, alpha-beta T cell (CL:0001044)
activated CD4-positive, CD25-positive, CCR4-positive, alpha-beta regulatory T cell, human (CL:0001048)
Immuno Cell Type:  Macrophages & monocytes
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   granulocyte (CL:0000094)
Immuno Process Associations
Immuno Process:  Barrier integrity
GO Annotations:  Associated to 4 GO processes
GO:0019064 fusion of virus membrane with host plasma membrane TAS
GO:0030260 entry into host cell TAS
GO:0046598 positive regulation of viral entry into host cell IDA
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GO:0001618 virus receptor activity IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 7 GO processes
GO:0030217 T cell differentiation IDA
GO:0042110 T cell activation IBA
GO:0045058 T cell selection IDA
GO:0050863 regulation of T cell activation IDA
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
GO:0035397 helper T cell enhancement of adaptive immune response IEA
GO:0042102 positive regulation of T cell proliferation IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
GO:0035397 helper T cell enhancement of adaptive immune response IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 5 GO processes
GO:0045657 positive regulation of monocyte differentiation IDA
GO:0050852 T cell receptor signaling pathway TAS
GO:0050863 regulation of T cell activation IDA
click arrow to show/hide IEA associations
GO:0035397 helper T cell enhancement of adaptive immune response IEA
GO:0042102 positive regulation of T cell proliferation IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 4 GO processes
GO:0030217 T cell differentiation IDA
GO:0030225 macrophage differentiation IMP
GO:0045058 T cell selection IDA
GO:0045657 positive regulation of monocyte differentiation IDA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 6 GO processes
GO:0019221 cytokine-mediated signaling pathway TAS
GO:0035723 interleukin-15-mediated signaling pathway IDA
GO:0042012 interleukin-16 receptor activity IDA
GO:0045086 positive regulation of interleukin-2 biosynthetic process NAS
GO:0097011 cellular response to granulocyte macrophage colony-stimulating factor stimulus IDA
click arrow to show/hide IEA associations
GO:0001816 cytokine production IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
click arrow to show/hide IEA associations
GO:0042102 positive regulation of T cell proliferation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 6 GO processes
GO:0030217 T cell differentiation IDA
GO:0042110 T cell activation IBA
GO:0045058 T cell selection IDA
GO:0050852 T cell receptor signaling pathway TAS
GO:0050863 regulation of T cell activation IDA
click arrow to show/hide IEA associations
GO:0042102 positive regulation of T cell proliferation IEA
General Comments
CD4 is a cell membrane-bound glycoprotein that belongs to the immunoglobulin superfamily of proteins. It plays an essential role in the immune response. CD4's major function is as a co-receptor of the T cell receptor (TCR), which facilitates TCR interaction with MHC class II molecule:antigen complexes on antigen presenting cells, which subsequently leads to activation of T helper cells and production/release of immune system modulators. The intracellular cytoplasmic tail of ligand-engaged CD4 recruits the tyrosine kinase Lck to initiate the signalling cascade that culminates in immune system modulation. CD4 is also the primary receptor for the human immunodeficiency virus-1 (HIV-1) envelope protein gp120, and this ligand-receptor interaction facilitates recruitment of additional co-receptors (CCR5 or CXCR4) which are required for viral infection of T cells.
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. Burkly LC, Olson D, Shapiro R, Winkler G, Rosa JJ, Thomas DW, Williams C, Chisholm P. (1992) Inhibition of HIV infection by a novel CD4 domain 2-specific monoclonal antibody. Dissecting the basis for its inhibitory effect on HIV-induced cell fusion. J. Immunol., 149 (5): 1779-87. [PMID:1380539]

2. Duan LW, Zhang H, Zhao MT, Sun JX, Chen WL, Lin JP, Liu XQ. (2017) A non-canonical binding interface in the crystal structure of HIV-1 gp120 core in complex with CD4. Sci Rep, 7: 46733. [PMID:28429756]

3. Helling B, König M, Dälken B, Engling A, Krömer W, Heim K, Wallmeier H, Haas J, Wildemann B, Fritz B et al.. (2015) A specific CD4 epitope bound by tregalizumab mediates activation of regulatory T cells by a unique signaling pathway. Immunol. Cell Biol., 93 (4): 396-405. [PMID:25512343]

4. Iacob SA, Iacob DG. (2017) Ibalizumab Targeting CD4 Receptors, An Emerging Molecule in HIV Therapy. Front Microbiol, 8: 2323. [PMID:29230203]

5. Kim YH, Duvic M, Obitz E, Gniadecki R, Iversen L, Osterborg A, Whittaker S, Illidge TM, Schwarz T, Kaufmann R et al.. (2007) Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood, 109 (11): 4655-62. [PMID:17311990]

6. Kon OM, Sihra BS, Loh LC, Barkans J, Compton CH, Barnes NC, Larché M, Kay AB. (2001) The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma. Eur. Respir. J., 18 (1): 45-52. [PMID:11510804]

7. König M, Rharbaoui F, Aigner S, Dälken B, Schüttrumpf J. (2016) Tregalizumab - A Monoclonal Antibody to Target Regulatory T Cells. Front Immunol, 7: 11. [PMID:26834751]

8. Mestel DS, Beyer M, Möbs M, Steinhoff M, Sterry W, Assaf C. (2008) Zanolimumab, a human monoclonal antibody targeting CD4 in the treatment of mycosis fungoides and Sézary syndrome. Expert Opin Biol Ther, 8 (12): 1929-39. [PMID:18990079]

9. van Vollenhoven RF, Keystone EC, Strand V, Pacheco-Tena C, Vencovský J, Behrens F, Racewicz A, Zipp D, Rharbaoui F, Wolter R et al.. (2018) Efficacy and safety of tregalizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase IIb, randomised, placebo-controlled trial. Ann. Rheum. Dis., 77 (4): 495-499. [PMID:29343509]

10. Villadsen LS, Skov L, Dam TN, Dagnaes-Hansen F, Rygaard J, Schuurman J, Parren PW, van de Winkel JG, Baadsgaard O. (2007) In situ depletion of CD4+ T cells in human skin by Zanolimumab. Arch. Dermatol. Res., 298 (9): 449-55. [PMID:17091277]

11. Wijdenes J. (2004) Humanized anti-cd4 antibody with immunosuppressive properties. Patent number: WO2004083247 A1. Assignee: Biotest Ag. Priority date: 21/03/2003. Publication date: 30/09/2004.

How to cite this page

CD molecules: CD4. Last modified on 07/08/2019. Accessed on 21/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2995.