programmed cell death 1 (CD279)

Target id: 2760

Nomenclature: programmed cell death 1 (CD279)

Abbreviated Name: PD-1

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

   GtoImmuPdb view: OFF :     programmed cell death 1 (CD279) has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 288 2q37.3 PDCD1 programmed cell death 1
Mouse 1 288 1 D Pdcd1 programmed cell death 1
Rat 1 287 9q36 Pdcd1 programmed cell death 1
Previous and Unofficial Names
SLEB2
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human PD-1 (Apo-PD-1).
PDB Id:  3RRQ
Resolution:  2.1Å
Species:  Human
References: 
Natural/Endogenous Ligands
programmed cell death 1 ligand 1 {Sp: Human}

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 Affinity Units Reference
pembrolizumab Hs Binding ~10.0 pKd 3
pKd ~10.0 (Kd ~1x10-10 M) [3]
BGB-A317 Hs Binding 9.8 pKd 4
pKd 9.8 (Kd 1.5x10-10 M) [4]
nivolumab Hs Binding 9.1 pKd 5,7-8
pKd 9.1 (Kd 7.3x10-10 M) [5,7-8]
Antibody Comments
The clinical potential of PD-1 blockade in immuno-oncology is reviewed in [7]. Binding affinity for BGB-A317 should be considered preliminary until reported in a peer reviewed article.
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
programmed cell death 1 ligand 1 {Sp: Human} Hs Binding - -
Immunopharmacology Comments
Immune checkpoint blockade in oncology:
Many types of cancer cells evolve mechanisms to evade control and elimination by the immune system. Such mechanisms can include inhibition of so-called 'immune checkpoints', which would normally be involved in the maintenance of immune homeostasis. An increasingly important area of clinical oncology research is the development of new agents which impede these evasion techniques, thereby switching immune vigilance back on, and effecting immune destruction of cancer cells. Three molecular targets of checkpoint inhibitors which are being extensively pursued are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Using antibody-based therapies targeting these pathways, clinical responses have been reported in various tumour types, including melanoma, renal cell carcinoma [10] and non-small cell lung cancer [6,9].

Pembrolizumab was the first-in-class, anti-PD-1 antibody to be approved by the US FDA, followed in quich succession by nivolumab. Clinical trials are ongoing wih pidilizumab (NCT02077959, NCT01952769).

Immune checkpoint blockade in Alzheimer's disease (AD): In mouse models of AD anti-PD-1 antibody treatment was used to induce immune checkpoint blockade. The biological response included an interferon (IFN)-γ-dependent systemic immune response and recruitment of monocyte-derived macrophages to the brain, which was associated with amyloid β plaque clearance and improved cognitive function. These results point to immune checkpoints as valid targets for therapeutic intervention in AD [2].

PD-1 as a new drug target for asthma:
Yu et al. (2016) [11] have identified high PD-1 expression in a population of innate lymphoid cell (ILC) progenitors and activated ILC2 cells. Antibody-induced depletion of PD-1 ILCs reduces cytokine levels in inflammation models, including reducing lung inflammation in a papain-induced asthma model. The authors suggest this may represent an alternative pathway for development of novel immunotherapies for immune disease prevention and control.
Immuno Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   activated CD4-positive, alpha-beta T cell (CL:0000896)
activated CD8-positive, alpha-beta T cell (CL:0000906)
Comment:  PD-1 expression is induced in murine T cells activated by stimulation through antigen receptors.
References:  1
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
Fraction C precursor B cell (CL:0002049)
Comment:  Expressed in pro-B cells and is thought to play a role in their differentiation. PD-1 expression is induced in murine B cells activated by stimulation through antigen receptors.
References:  1
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process ID:  4
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  T cell costimulation (GO:0031295) TAS
positive regulation of T cell apoptotic process (GO:0070234) IDA
References: 
Immuno Process:  Immune regulation
Immuno Process ID:  6
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  negative regulation of tolerance induction (GO:0002644) IEA
T cell costimulation (GO:0031295) TAS
References: 
Immuno Process:  Chemotaxis & migration
Immuno Process ID:  10
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  T cell costimulation (GO:0031295) TAS
References: 
Immuno Process:  Cellular signalling
Immuno Process ID:  11
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  T cell costimulation (GO:0031295) TAS
References: 
Immuno Process:  Immune system development
Immuno Process ID:  8
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  negative regulation of tolerance induction (GO:0002644) IEA
References: 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Alzheimer disease
Synonyms: Alzheimer's disease [Disease Ontology: DOID:10652]
Disease Ontology: DOID:10652
OMIM: 104300
Role: 
References:  2
Disease:  Multiple Sclerosis
Disease Ontology: DOID:2377
OMIM: 126200
Orphanet: ORPHA802
Disease:  Systemic lupus erythematosus, susceptibility to, 2; SLEB2
Synonyms: Systemic lupus erythematosus [Orphanet: ORPHA536] [Disease Ontology: DOID:9074]
Disease Ontology: DOID:9074
OMIM: 605218
Orphanet: ORPHA536
General Comments
The endogenous ligands for human PD-1 are programmed cell death 1 ligand 1 (PD-L1 aka CD274 (CD274, Q9NZQ7) and programmed cell death 1 ligand 2 (PD-L2; PDCD1LG2). These ligands are cell surface peptides, normally involved in immune system regulation.

References

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1. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T. (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol.8 (5): 765-72. [PMID:8671665]

2. Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, Kertser A, David E, Amit I, Schwartz M. (2016) PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat. Med.22 (2): 135-7. [PMID:26779813]

3. Carven GJ, Van Eenennaam H, Dulos GJ. (2010) Antibodies to human programmed death receptor PD-1. Patent number: US20100266617. Assignee: Organon NV. Priority date: 13/06/2008. Publication date: 21/10/2010.

4. Desai J, Markman B, Sandhu SK, Gan HK, Friedlander M, Tran B, Meniawy T, Boolell V, Colyer D, Norris C et al.. A phase I dose-escalation study of BGB-A317, an anti-programmed death-1 (PD-1) mAb in patients with advanced solid tumors. Accessed on 06/06/2017. Modified on 06/06/2017. http://meetinglibrary.asco.org, http://meetinglibrary.asco.org/record/125804/abstract

5. Hall RD, Gray JE, Chiappori AA. (2013) Beyond the standard of care: a review of novel immunotherapy trials for the treatment of lung cancer. Cancer Control20 (1): 22-31. [PMID:23302904]

6. Johnson DB, Rioth MJ, Horn L. (2014) Immune Checkpoint Inhibitors in NSCLC. Curr Treat Options Oncol,  [Epub ahead of print]. [PMID:25096781]

7. Kline J, Gajewski TF. (2010) Clinical development of mAbs to block the PD1 pathway as an immunotherapy for cancer. Curr Opin Investig Drugs11 (12): 1354-9. [PMID:21154117]

8. Korman AJ, Srinivasan M, Wang C, Selby MJ, Chen B, Cardarelli JM. (2006) Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics. Patent number: WO2006121168. Assignee: Ono Pharmaceutical Co. Priority date: 09/05/2005. Publication date: 02/03/2015.

9. Malas S, Harrasser M, Lacy KE, Karagiannis SN. (2014) Antibody therapies for melanoma: New and emerging opportunities to activate immunity (Review). Oncol. Rep.32 (3): 875-86. [PMID:24969320]

10. Pal SK, Hu A, Chang M, Figlin RA. (2014) Programmed death-1 inhibition in renal cell carcinoma: clinical insights and future directions. Clin Adv Hematol Oncol12 (2): 90-9. [PMID:24892254]

11. Yu Y, Tsang JC, Wang C, Clare S, Wang J, Chen X, Brandt C, Kane L, Campos LS, Lu L et al.. (2016) Single-cell RNA-seq identifies a PD-1(hi) ILC progenitor and defines its developmental pathway. Nature,  [Epub ahead of print]. [PMID:27749818]

How to cite this page

Other immune checkpoint proteins: programmed cell death 1 (CD279). Last modified on 09/08/2017. Accessed on 23/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2760.