Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers
Blocking the immunoinhibitory PD-1:PD-L1 pathway using monoclonal antibodies has led to dramatic clinical responses by reversing tumor immune evasion and provoking robust and durable antitumor responses. Anti-PD-1 antibodies have now been approved for the treatment of melanoma, and are being clinica...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116300233 |
| _version_ | 1818036211667697664 |
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| author | Aaron Prodeus Aws Abdul-Wahid Nicholas W Fischer Eric H-B Huang Marzena Cydzik Jean Gariépy |
| author_facet | Aaron Prodeus Aws Abdul-Wahid Nicholas W Fischer Eric H-B Huang Marzena Cydzik Jean Gariépy |
| author_sort | Aaron Prodeus |
| collection | DOAJ |
| description | Blocking the immunoinhibitory PD-1:PD-L1 pathway using monoclonal antibodies has led to dramatic clinical responses by reversing tumor immune evasion and provoking robust and durable antitumor responses. Anti-PD-1 antibodies have now been approved for the treatment of melanoma, and are being clinically tested in a number of other tumor types as both a monotherapy and as part of combination regimens. Here, we report the development of DNA aptamers as synthetic, nonimmunogenic antibody mimics, which bind specifically to the murine extracellular domain of PD-1 and block the PD-1:PD-L1 interaction. One such aptamer, MP7, functionally inhibits the PD-L1-mediated suppression of IL-2 secretion in primary T-cells. A PEGylated form of MP7 retains the ability to block the PD-1:PD-L1 interaction, and significantly suppresses the growth of PD-L1+ colon carcinoma cells in vivo with a potency equivalent to an antagonistic anti-PD-1 antibody. Importantly, the anti-PD-1 DNA aptamer treatment was not associated with off-target TLR-9-related immune responses. Due to the inherent advantages of aptamers including their lack of immunogenicity, low cost, long shelf life, and ease of synthesis, PD-1 antagonistic aptamers may represent an attractive alternative over antibody-based anti PD-1 therapeutics. |
| first_indexed | 2024-12-10T07:07:21Z |
| format | Article |
| id | doaj.art-5cce4f9ed51b44f48b78333b4a41f536 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-10T07:07:21Z |
| publishDate | 2015-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-5cce4f9ed51b44f48b78333b4a41f5362022-12-22T01:58:09ZengElsevierMolecular Therapy: Nucleic Acids2162-25312015-01-014C10.1038/mtna.2015.11Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated CancersAaron Prodeus0Aws Abdul-Wahid1Nicholas W Fischer2Eric H-B Huang3Marzena Cydzik4Jean Gariépy5Department of Medical Biophysics, University of Toronto, Toronto, Ontario, CanadaPhysical Sciences, Sunnybrook Research Institute, Toronto, Ontario, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, Ontario, CanadaPhysical Sciences, Sunnybrook Research Institute, Toronto, Ontario, CanadaPhysical Sciences, Sunnybrook Research Institute, Toronto, Ontario, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, Ontario, CanadaBlocking the immunoinhibitory PD-1:PD-L1 pathway using monoclonal antibodies has led to dramatic clinical responses by reversing tumor immune evasion and provoking robust and durable antitumor responses. Anti-PD-1 antibodies have now been approved for the treatment of melanoma, and are being clinically tested in a number of other tumor types as both a monotherapy and as part of combination regimens. Here, we report the development of DNA aptamers as synthetic, nonimmunogenic antibody mimics, which bind specifically to the murine extracellular domain of PD-1 and block the PD-1:PD-L1 interaction. One such aptamer, MP7, functionally inhibits the PD-L1-mediated suppression of IL-2 secretion in primary T-cells. A PEGylated form of MP7 retains the ability to block the PD-1:PD-L1 interaction, and significantly suppresses the growth of PD-L1+ colon carcinoma cells in vivo with a potency equivalent to an antagonistic anti-PD-1 antibody. Importantly, the anti-PD-1 DNA aptamer treatment was not associated with off-target TLR-9-related immune responses. Due to the inherent advantages of aptamers including their lack of immunogenicity, low cost, long shelf life, and ease of synthesis, PD-1 antagonistic aptamers may represent an attractive alternative over antibody-based anti PD-1 therapeutics.http://www.sciencedirect.com/science/article/pii/S2162253116300233cancerDNA aptamerimmunotherapyPD-1 |
| spellingShingle | Aaron Prodeus Aws Abdul-Wahid Nicholas W Fischer Eric H-B Huang Marzena Cydzik Jean Gariépy Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers Molecular Therapy: Nucleic Acids cancer DNA aptamer immunotherapy PD-1 |
| title | Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers |
| title_full | Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers |
| title_fullStr | Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers |
| title_full_unstemmed | Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers |
| title_short | Targeting the PD-1/PD-L1 Immune Evasion Axis With DNA Aptamers as a Novel Therapeutic Strategy for the Treatment of Disseminated Cancers |
| title_sort | targeting the pd 1 pd l1 immune evasion axis with dna aptamers as a novel therapeutic strategy for the treatment of disseminated cancers |
| topic | cancer DNA aptamer immunotherapy PD-1 |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116300233 |
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