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CD28

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Target id: 2863

Nomenclature: CD28

Family: Other immune checkpoint proteins, CD molecules

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 220 2q33.2 CD28 CD28 molecule
Mouse 1 218 1 30.52 cM Cd28 CD28 antigen
Rat 1 218 9q32 Cd28 Cd28 molecule
Previous and Unofficial Names Click here for help
cluster of differentiation 28 | CD28 antigen (Tp44)
Database Links Click here for help
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file go icon to follow link

Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
lulizumab pegol Peptide Primary target of this compound Immunopharmacology Ligand Hs Binding 9.3 – 9.4 pKd 3
pKd 9.3 – 9.4 (Kd 5.1x10-10 – 3.6x10-10 M) [3]
Description: Note that this Kd value was determined using the 'naked' binding component, in the absence of PEGylation.
Immunopharmacology Comments
CD28 is expressed on the surface of T cells and is required for the co-stimulatory signal essential for the activation, proliferation and survival of T cells, and Th2 cell development. CD28 acts in concert with the T cell receptor to stimulate cytokine release (promotes IL-2 production). CD28 binds the the B7 proteins CD80 and CD86 on the surface of antigen presenting cells to effect a co-stimulatory signal to T cells. In contrast, CTLA-4 delivers a co-inhibitory signal via CD80/CD86 [1]. These two opposing signals are part of a complex network of positive and negative co-stimulatory signals, that integrate to modulate immune responses. Targeted blockade of CD28 is predicted to be more clinically effective than the anti-CTLA-4 strategy as this mechanism exclusively inhibits T cell co-stimulation.
As a drug target, CD28 modulation is being investigated as a treatment for autoimmume conditions. In 2006 an anti-CD28 antibody with superagonist activity (TGN1412) caused catastrophic organ failure in clinical trial participants due to 'cytokine storm' (multiple cytokine-release syndrome) in response to massive systemic T cell activation and inflammatory response [4]. More recently developed anti-CD28 antibodies are modified in ways which prevent co-stimulation and cytokine release, and result only in T cell anergy or apoptosis [3]. FR104, an antagonist anti-CD28 monovalent PEGylated Fab' construct, has reported efficacy as an alternative immunosuppression strategy to B7 antagonists for kidney transplant recipients [2]. FR104 has been tested in the nonhuman primate GvHD model, with results indicating that this strategy would require close scrutiny of the risk/benefit profile before use in humans with GvHD [5]. FR104 has completed a Phase 1 first-in-human trial (NCT02800811) in healthy subjects.
Cell Type Associations
Immuno Cell Type:  T cells
Immuno Process Associations
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 8 GO processes
GO:0031295 T cell costimulation TAS
GO:0042102 positive regulation of T cell proliferation IDA
GO:0042110 T cell activation IGI
GO:0045066 regulatory T cell differentiation IDA
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GO:0045060 negative thymic T cell selection IEA
GO:0045589 regulation of regulatory T cell differentiation IEA
GO:0046641 positive regulation of alpha-beta T cell proliferation IEA
GO:0048304 positive regulation of isotype switching to IgG isotypes IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 7 GO processes
GO:0031295 T cell costimulation TAS
GO:0042102 positive regulation of T cell proliferation IDA
click arrow to show/hide IEA associations
GO:0002863 positive regulation of inflammatory response to antigenic stimulus IEA
GO:0045589 regulation of regulatory T cell differentiation IEA
GO:0046641 positive regulation of alpha-beta T cell proliferation IEA
GO:0048304 positive regulation of isotype switching to IgG isotypes IEA
GO:0050852 T cell receptor signaling pathway IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 4 GO processes
GO:0045066 regulatory T cell differentiation IDA
click arrow to show/hide IEA associations
GO:0045060 negative thymic T cell selection IEA
GO:0045589 regulation of regulatory T cell differentiation IEA
GO:0048304 positive regulation of isotype switching to IgG isotypes IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 3 GO processes
GO:0032733 positive regulation of interleukin-10 production IDA
GO:0032753 positive regulation of interleukin-4 production IDA
GO:0042089 cytokine biosynthetic process TAS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 3 GO processes
GO:0031295 T cell costimulation TAS
GO:0042102 positive regulation of T cell proliferation IDA
click arrow to show/hide IEA associations
GO:0046641 positive regulation of alpha-beta T cell proliferation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 9 GO processes
GO:0031295 T cell costimulation TAS
GO:0042102 positive regulation of T cell proliferation IDA
GO:0042110 T cell activation IGI
GO:0045066 regulatory T cell differentiation IDA
click arrow to show/hide IEA associations
GO:0045060 negative thymic T cell selection IEA
GO:0045589 regulation of regulatory T cell differentiation IEA
GO:0046641 positive regulation of alpha-beta T cell proliferation IEA
GO:0048304 positive regulation of isotype switching to IgG isotypes IEA
GO:0050852 T cell receptor signaling pathway IEA
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002863 positive regulation of inflammatory response to antigenic stimulus IEA
GO:0048304 positive regulation of isotype switching to IgG isotypes IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0048304 positive regulation of isotype switching to IgG isotypes IEA
General Comments
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. Alegre ML, Frauwirth KA, Thompson CB. (2001) T-cell regulation by CD28 and CTLA-4. Nat. Rev. Immunol., 1 (3): 220-8. [PMID:11905831]

2. Poirier N, Dilek N, Mary C, Ville S, Coulon F, Branchereau J, Tillou X, Charpy V, Pengam S, Nerriere-Daguin V et al.. (2015) FR104, an antagonist anti-CD28 monovalent fab' antibody, prevents alloimmunization and allows calcineurin inhibitor minimization in nonhuman primate renal allograft. Am. J. Transplant., 15 (1): 88-100. [PMID:25488654]

3. Suchard SJ, Davis PM, Kansal S, Stetsko DK, Brosius R, Tamura J, Schneeweis L, Bryson J, Salcedo T, Wang H et al.. (2013) A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety. J. Immunol., 191 (9): 4599-610. [PMID:24081989]

4. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med., 355 (10): 1018-28. [PMID:16908486]

5. Watkins BK, Tkachev V, Furlan SN, Hunt DJ, Betz K, Yu A, Brown M, Poirier N, Zheng HB, Taraseviciute A et al.. (2018) CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates. J. Clin. Invest., 128 (9): 3991-4007. [PMID:30102255]

How to cite this page

Other immune checkpoint proteins: CD28. Last modified on 07/08/2019. Accessed on 24/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2863.