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From Proteopedia
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| - | + | ==Structure of PD-1== | |
| + | <StructureSection load='3bik' size='350' side='right' caption='PD-1 and its ligand Pd-L1 (PDB entry [[3bik]])' scene=''> </StructureSection> | ||
== General presentation of the protein: == | == General presentation of the protein: == | ||
| - | The PD-1 protein, also known as CD279, is a program cell-death 1 protein which plays a particular role in the activation of T-lymphocytes. This cell surface receptor | + | The PD-1 protein, also known as CD279, is a program cell-death 1 protein which plays a particular role in the activation of T-lymphocytes. |
| - | Even if it structure is not yet totally characterized, PD-1 seems to be a promising target | + | This protein of 288 amino acids is encoded by a cDNA gene of 2,106 base pairs long located in the chromosome 2 for human. This cell surface receptor can be found on pro-B cells and T cells and belongs to the immunoglobulin super family. It can bind two ligands: PD-L1 and PD-L2 and when it is related to PD-L2, it results an inhibition of T-cells and cytokine production. |
| + | Even if it structure is not yet totally characterized, PD-1 seems to be a promising target for clinical applications. | ||
== History : == | == History : == | ||
| - | PD-1 cDNA was discovered in 1992 by Ishida et | + | PD-1 cDNA was discovered in 1992 by Ishida et al. Thanks to the studies on PD-1-deficient mice on the C57BL/6 background, PD-1 begun to be understood, even if its precise function still unknown at this time. Still, the role of PD-1 in deficiency and autoimmunity was suggested. |
| + | In 1994, Shinohara et al. (1994) succeeded in characterizing the human homolog of the mouse gene and the similarity was of 60% for amino acids, with a well-conserved tyrosine-kinase association motif. | ||
| + | In 1997, Finger et al. (1997) achieved the complete sequencing of the cDNA of the PD-1 gene. | ||
| + | Since 2014 and 2015, some drugs are proposed to prevent the binding of the ligands of PD-1 and favorized its role in the activation of T-lymphocytes: PD-1 is now a new promising target for immunotherapy and cancer research. | ||
== Clinical applications: == | == Clinical applications: == | ||
| - | PD-1 negatively regulates immune response and is used for immunotherapy and particularly for cancers. | + | PD-1 negatively regulates immune response and is used for immunotherapy and particularly for cancers and as tumor repressor. |
| - | Nivolumab (Opdivo, Bristol-Myers Squibb), an antibody-drug, was then developed to block the activity of this receptor and is given to treat metastatic melanomas. This drug prevents the binding of the PD-1 ligands | + | Nivolumab (Opdivo, Bristol-Myers Squibb), an antibody-drug, was then developed to block the activity of this receptor and is given to treat metastatic melanomas. This drug prevents the binding of the PD-1 ligands which permits T-cells to work. |
| - | For the same applications, Pembrolizumab (Keytruda, MK-3475, Merck) has been developed and is used since March 2015 in the UK for advanced melanoma and it is in the clinical trials in the US. | + | For the same applications, Pembrolizumab (Keytruda, MK-3475, Merck)) has been developed and is used since March 2015 in the UK for advanced melanoma and it is in the clinical trials in the US. |
Others drugs are being developed such as Pidilizumab (CT-011, Cure Tech), BMS 936559 (Bristol Myers Squibb), and MPDL328OA (Roche). | Others drugs are being developed such as Pidilizumab (CT-011, Cure Tech), BMS 936559 (Bristol Myers Squibb), and MPDL328OA (Roche). | ||
Revision as of 20:25, 28 January 2016
Contents |
Structure of PD-1
|
General presentation of the protein:
The PD-1 protein, also known as CD279, is a program cell-death 1 protein which plays a particular role in the activation of T-lymphocytes. This protein of 288 amino acids is encoded by a cDNA gene of 2,106 base pairs long located in the chromosome 2 for human. This cell surface receptor can be found on pro-B cells and T cells and belongs to the immunoglobulin super family. It can bind two ligands: PD-L1 and PD-L2 and when it is related to PD-L2, it results an inhibition of T-cells and cytokine production. Even if it structure is not yet totally characterized, PD-1 seems to be a promising target for clinical applications.
History :
PD-1 cDNA was discovered in 1992 by Ishida et al. Thanks to the studies on PD-1-deficient mice on the C57BL/6 background, PD-1 begun to be understood, even if its precise function still unknown at this time. Still, the role of PD-1 in deficiency and autoimmunity was suggested. In 1994, Shinohara et al. (1994) succeeded in characterizing the human homolog of the mouse gene and the similarity was of 60% for amino acids, with a well-conserved tyrosine-kinase association motif. In 1997, Finger et al. (1997) achieved the complete sequencing of the cDNA of the PD-1 gene. Since 2014 and 2015, some drugs are proposed to prevent the binding of the ligands of PD-1 and favorized its role in the activation of T-lymphocytes: PD-1 is now a new promising target for immunotherapy and cancer research.
Clinical applications:
PD-1 negatively regulates immune response and is used for immunotherapy and particularly for cancers and as tumor repressor. Nivolumab (Opdivo, Bristol-Myers Squibb), an antibody-drug, was then developed to block the activity of this receptor and is given to treat metastatic melanomas. This drug prevents the binding of the PD-1 ligands which permits T-cells to work. For the same applications, Pembrolizumab (Keytruda, MK-3475, Merck)) has been developed and is used since March 2015 in the UK for advanced melanoma and it is in the clinical trials in the US. Others drugs are being developed such as Pidilizumab (CT-011, Cure Tech), BMS 936559 (Bristol Myers Squibb), and MPDL328OA (Roche).
