CD4

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 2995

Nomenclature: CD4

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 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

Previous and Unofficial Names

CD4 antigen (p55) | T-cell surface glycoprotein CD4 | cluster of differentiation 4

Database Links
Alphafold	P01730 (Hs), P06332 (Mm), P05540 (Rn)
ChEMBL Target	CHEMBL2754 (Hs)
Ensembl Gene	ENSG00000010610 (Hs), ENSMUSG00000023274 (Mm), ENSRNOG00000016294 (Rn)
Entrez Gene	920 (Hs), 12504 (Mm), 24932 (Rn)
Human Protein Atlas	ENSG00000010610 (Hs)
KEGG Gene	hsa:920 (Hs), mmu:12504 (Mm), rno:24932 (Rn)
OMIM	186940 (Hs)
Pharos	P01730 (Hs)
RefSeq Nucleotide	NM_000616 (Hs), NM_013488 (Mm), NM_012705 (Rn)
RefSeq Protein	NP_000607 (Hs), NP_038516 (Mm), NP_036837 (Rn)
UniProtKB	P01730 (Hs), P06332 (Mm), P05540 (Rn)
Wikipedia	CD4 (Hs)

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Antibodies

Key to terms and symbols

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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.

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:

Immuno Process:

Immuno Process:

Immuno Process:

Immuno Process:

Immune system development

Immuno Process:

Cytokine production & signalling

Immuno Process:

Chemotaxis & migration

Immuno Process:

Cellular signalling

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.

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.