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target has curated data in GtoImmuPdb
Target id: 2760
Nomenclature: programmed cell death 1 (CD279)
Abbreviated Name: PD-1
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 | |
Alphafold | Q15116 (Hs), Q02242 (Mm) |
CATH/Gene3D | 2.60.40.10 |
ChEMBL Target | CHEMBL3307223 (Hs), CHEMBL4630756 (Mm) |
Ensembl Gene | ENSG00000188389 (Hs), ENSMUSG00000026285 (Mm), ENSRNOG00000019043 (Rn) |
Entrez Gene | 5133 (Hs), 18566 (Mm), 301626 (Rn) |
Human Protein Atlas | ENSG00000188389 (Hs) |
KEGG Gene | hsa:5133 (Hs), mmu:18566 (Mm), rno:301626 (Rn) |
OMIM | 600244 (Hs) |
Pharos | Q15116 (Hs) |
RefSeq Nucleotide | NM_005018 (Hs), NM_008798 (Mm), NM_001106927 (Rn) |
RefSeq Protein | NP_005009 (Hs), NP_032824 (Mm), NP_001100397 (Rn) |
UniProtKB | Q15116 (Hs), Q02242 (Mm) |
Wikipedia | PDCD1 (Hs) |
Selected 3D Structures | |||||||||||||
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Natural/Endogenous Ligands |
programmed cell death 1 ligand 1 {Sp: Human} |
Download all structure-activity data for this target as a CSV file
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
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Antibodies | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Antibody Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The clinical potential of PD-1 blockade in immuno-oncology is reviewed in [19]. Binding affinity for tislelizumab (BGB-A317) should be considered preliminary until reported in a peer reviewed article. |
Other Binding Ligands | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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 [25] and non-small cell lung cancer [18,23]. Pembrolizumab was the first-in-class, anti-PD-1 antibody to be approved by the US FDA (in 2014), followed in quick succession by nivolumab, and then by cemiplimab in 2018. The number of anti-PD-1 antibodies in clinical use continues to grow. Synthetic small-molecule PD-1 inhibitors are in development e.g. Curis' CA-170 which is an orally active PD-1/VISTA antagonist in Phase 1 clinical development (NCT02812875) in patients with advanced solid tumours and lymphomas. Recent articles and reviews provide up-to-date information covering the progress that has been made in developing peptide-based and nonpeptidic small-molecule inhibitors of the PD-1/PD-L1 pathway:- Wang et al. (2018) [35], Shaabani et al. (2018) [29], and Chen et al. (2019) [6]. 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) [36] 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. The PD-1/PD-L1 axis in the anti-inflammatory effects of mesenchymal stromal cell (MSC) delivery as a novel anti-rejection therapy. A study that investigated the potential of using MSCs as prophylactic and therapeutic agents against the acute rejection of lung grafts (in rats) identified an MSC-induced upregulation of PD-L1 expression by alveolar cells as a major contributory factor to the anti-inflammatory effects observed, which implicates PD-1/PD-L1 driven inhibition of immune responses in the beneficial effects of MSC therapy [17]. A second significant contributory factor identified was down-regulation of pro-inflammatory IL-17A production by infiltrating effector T cells in the allografts. |
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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. The PD-1 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. |
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. Beldi-Ferchiou A, Lambert M, Dogniaux S, Vély F, Vivier E, Olive D, Dupuy S, Levasseur F, Zucman D, Lebbé C et al.. (2016) PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget, 7 (45): 72961-72977. [PMID:27662664]
4. Burova E, Hermann A, Waite J, Potocky T, Lai V, Hong S, Liu M, Allbritton O, Woodruff A, Wu Q et al.. (2017) Characterization of the Anti-PD-1 Antibody REGN2810 and Its Antitumor Activity in Human PD-1 Knock-In Mice. Mol Cancer Ther, 16 (5): 861-870. [PMID:28265006]
5. 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.
6. Chen T, Li Q, Liu Z, Chen Y, Feng F, Sun H. (2019) Peptide-based and small synthetic molecule inhibitors on PD-1/PD-L1 pathway: A new choice for immunotherapy?. Eur J Med Chem, 161: 378-398. [PMID:30384043]
7. Della Chiesa M, Pesce S, Muccio L, Carlomagno S, Sivori S, Moretta A, Marcenaro E. (2016) Features of Memory-Like and PD-1(+) Human NK Cell Subsets. Front Immunol, 7: 351. [PMID:27683578]
8. 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
9. Ekimova VM, Korzhavin DV, Chernykh YS, Nemankin TA, Solovyev VV, Vladamirova Ak, Bulankina IA, Diduk SV, Ustigov IL, Artiukhova MV et al.. (2021) Anti-PD-1 antibodies, method for producing same and method for using same. Patent number: US11136408B2. Assignee: Closed Joint-Stock Co "biocad", Biocad JSC. Priority date: 04/07/2017. Publication date: 05/10/2021.
10. FDA. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. Accessed on 18/04/2018. Modified on 18/04/2018. www.fda.gov, https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm604685.htm?utm_campaign=Oncology%204%2F16%2F2018&utm_medium=email&utm_source=Eloqua&elqTrackId=461a88586a9a4db284ceb54da34a6a23&elq=8b10e118e0b249beb2807c129fc264e8&elqaid=3169&elqat=1&elqCampaignId=2374
11. Freeman GJ, Sharpe AH, Blattler WA, Mataraza JM, Sabatos-Peyton CA, Chang HW, Frey GJ. (2017) Antibody molecules to PD-1 and uses thereof. Patent number: US9683048B2. Assignee: Novartis AG Harvard College, Dana-Farber Cancer Institute Inc. Priority date: 24/01/2014. Publication date: 20/06/2017.
12. Fu J, Wang F, Dong LH, Zhang J, Deng CL, Wang XL, Xie XY, Zhang J, Deng RX, Zhang LB et al.. (2017) Preclinical evaluation of the efficacy, pharmacokinetics and immunogenicity of JS-001, a programmed cell death protein-1 (PD-1) monoclonal antibody. Acta Pharmacol Sin, 38 (5): 710-718. [PMID:28317872]
13. 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 Control, 20 (1): 22-31. [PMID:23302904]
14. Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault MC, Trevino TN, Azimi CS, Scheer AK, Randolph HE, Thompson TW et al.. (2018) Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest, 128 (10): 4654-4668. [PMID:30198904]
15. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B et al.. (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature, 545 (7652): 60-65. [PMID:28397821]
16. Huang Z, Pang X, Zhong T, Qu T, Chen N, Ma S, He X, Xia D, Wang M, Xia M et al.. (2022) Penpulimab, an Fc-Engineered IgG1 Anti-PD-1 Antibody, With Improved Efficacy and Low Incidence of Immune-Related Adverse Events. Front Immunol, 13: 924542. [PMID:35833116]
17. Ishibashi N, Watanabe T, Kanehira M, Watanabe Y, Hoshikawa Y, Notsuda H, Noda M, Sakurada A, Ohkouchi S, Kondo T et al.. (2018) Bone marrow mesenchymal stromal cells protect allograft lung transplants from acute rejection via the PD-L1/IL-17A axis. Surg Today, 48 (7): 726-734. [PMID:29546496]
18. Johnson DB, Rioth MJ, Horn L. (2014) Immune checkpoint inhibitors in NSCLC. Curr Treat Options Oncol, 15 (4): 658-69. [PMID:25096781]
19. Kline J, Gajewski TF. (2010) Clinical development of mAbs to block the PD1 pathway as an immunotherapy for cancer. Curr Opin Investig Drugs, 11 (12): 1354-9. [PMID:21154117]
20. 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.
21. Liu Y, Cheng Y, Xu Y, Wang Z, Du X, Li C, Peng J, Gao L, Liang X, Ma C. (2017) Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene, 36 (44): 6143-6153. [PMID:28692048]
22. Lou B, Wei H, Yang F, Wang S, Yang B, Zheng Y, Zhu J, Yan S. (2021) Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer. Front Oncol, 11: 736955. [PMID:34604074]
23. 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]
24. Oaknin A, Tinker AV, Gilbert L, Samouëlian V, Mathews C, Brown J, Barretina-Ginesta MP, Moreno V, Gravina A, Abdeddaim C et al.. (2020) Clinical Activity and Safety of the Anti-Programmed Death 1 Monoclonal Antibody Dostarlimab for Patients With Recurrent or Advanced Mismatch Repair-Deficient Endometrial Cancer: A Nonrandomized Phase 1 Clinical Trial. JAMA Oncol, 6 (11): 1766-1772. [PMID:33001143]
25. 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 Oncol, 12 (2): 90-9. [PMID:24892254]
26. Pang X, Huang Z, Zhong T, Zhang P, Wang ZM, Xia M, Li B. (2023) Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity. MAbs, 15 (1): 2180794. [PMID:36872527]
27. Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, Moretta L, Moretta A, Marcenaro E. (2017) Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization. J Allergy Clin Immunol, 139 (1): 335-346.e3. [PMID:27372564]
28. Sasikumar PGN, Ramachandra M, Vadlamani SK, Vemula KR, Satyam LK, Subbarao K, Shrimali KR, Kendepu S. (2011) Immunosuppression modulating compounds. Patent number: US20110318373A1. Assignee: Aurigene Discovery Technologies Ltd. Priority date: 25/06/2010. Publication date: 29/12/2011.
29. Shaabani S, Huizinga HPS, Butera R, Kouchi A, Guzik K, Magiera-Mularz K, Holak TA, Dömling A. (2018) A patent review on PD-1/PD-L1 antagonists: small molecules, peptides, and macrocycles (2015-2018). Expert Opin Ther Pat, 28 (9): 665-678. [PMID:30107136]
30. Shah K, Smith DH, La Motte-Mohs R, Johnson LS, Moore PA, Bonvini E, Koenig S. (2017) Pd-1-binding molecules and methods use thereof. Patent number: WO2017019846A1. Assignee: Macrogenics, Inc.. Priority date: 30/07/2015. Publication date: 02/02/2017.
31. Taylor S, Huang Y, Mallett G, Stathopoulou C, Felizardo TC, Sun MA, Martin EL, Zhu N, Woodward EL, Elias MS et al.. (2017) PD-1 regulates KLRG1+ group 2 innate lymphoid cells. J Exp Med, 214 (6): 1663-1678. [PMID:28490441]
32. Tumino N, Martini S, Munari E, Scordamaglia F, Besi F, Mariotti FR, Bogina G, Mingari MC, Vacca P, Moretta L. (2019) Presence of innate lymphoid cells in pleural effusions of primary and metastatic tumors: Functional analysis and expression of PD-1 receptor. Int J Cancer, 145 (6): 1660-1668. [PMID:30856277]
33. Vacca P, Pesce S, Greppi M, Fulcheri E, Munari E, Olive D, Mingari MC, Moretta A, Moretta L, Marcenaro E. (2019) PD-1 is expressed by and regulates human group 3 innate lymphoid cells in human decidua. Mucosal Immunol, 12 (3): 624-631. [PMID:30755717]
34. Vari F, Arpon D, Keane C, Hertzberg MS, Talaulikar D, Jain S, Cui Q, Han E, Tobin J, Bird R et al.. (2018) Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood, 131 (16): 1809-1819. [PMID:29449276]
35. Wang T, Wu X, Guo C, Zhang K, Xu J, Li Z, Jiang S. (2019) Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signaling Pathway. J Med Chem, 62 (4): 1715-1730. [PMID:30247903]
36. 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-1hi ILC progenitor and defines its development pathway. Nature, 539 (7627): 102-106. [PMID:27749818]
37. Zak KM, Kitel R, Przetocka S, Golik P, Guzik K, Musielak B, Dömling A, Dubin G, Holak TA. (2015) Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1. Structure, 23 (12): 2341-2348. [PMID:26602187]
38. Zhang S, Zhang M, Wu W, Yuan Z, Tsun A, Wo M, Chen B, Li J, Miao X, Yu D et al.. (2018) Preclinical characterization of Sintilimab, a fully human anti-PD-1 therapeutic monoclonal antibody for cancer. Antibody Therapeutics, 1 (2): 65–73. DOI: 10.1093/abt/tby005
39. Zhong T, Huang Z, Pang X, Jin C, He X, Xia Y, Li B, Min J. (2022) AK112, a tetravalent bispecific antibody targeting PD-1 and VEGF, enhances binding avidity and functional activities and elicits potent anti-tumor efficacy in pre-clinical studies. J Immunother Cancer, 10 (Suppl 2): A546–A547 Abstract. DOI: 10.1136/jitc-2022-SITC2022.0521
Other immune checkpoint proteins: programmed cell death 1 (CD279). Last modified on 03/06/2024. Accessed on 15/11/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2760.