CD28

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 2863

Nomenclature: CD28

Family: Other immune checkpoint proteins, CD molecules

Gene and Protein Information
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
cluster of differentiation 28 \| CD28 antigen (Tp44)

Database Links
Alphafold	P10747 (Hs), P31041 (Mm), P31042 (Rn)
CATH/Gene3D	2.60.40.10
ChEMBL Target	CHEMBL5191 (Hs)
Ensembl Gene	ENSG00000178562 (Hs), ENSMUSG00000026012 (Mm), ENSRNOG00000010283 (Rn)
Entrez Gene	940 (Hs), 12487 (Mm), 25660 (Rn)
Human Protein Atlas	ENSG00000178562 (Hs)
KEGG Gene	hsa:940 (Hs), mmu:12487 (Mm), rno:25660 (Rn)
OMIM	186760 (Hs)
Pharos	P10747 (Hs)
RefSeq Nucleotide	NM_006139 (Hs), NM_007642 (Mm), NM_013121 (Rn)
RefSeq Protein	NP_006130 (Hs), NP_031668 (Mm), NP_037253 (Rn)
UniProtKB	P10747 (Hs), P31041 (Mm), P31042 (Rn)
Wikipedia	CD28 (Hs)

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Antibodies

Key to terms and symbols

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Antibody											Sp.	Action	Value	Parameter	Reference
lulizumab pegol											Hs	Binding	9.3 – 9.4	pK_d	3
⤷	pK_d 9.3 – 9.4 (K_d 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.

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)

Immuno Process:

Immune regulation

Immuno Process:

Immune system development

Immuno Process:

Cytokine production & signalling

Immuno Process:

Chemotaxis & migration

Immuno Process:

Cellular signalling

Immuno Process:

Inflammation

Immuno Process:

B cell (activation)

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 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2863.

CD28

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References

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