TLR9-mediated activation of dendritic cells by CD32 targeting for the generation of highly immunostimulatory vaccines
The rational for designing dendritic cell (DC)-targeted immunotherapies is their central role in orchestrating immunity. Most studies addressing antigen-targeting to DCs for eliciting T cell responses have employed ex-vivo matured DCs derived from monocytes or myeloid DCs isolated from peripheral bl...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Human Vaccines & Immunotherapeutics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/21645515.2018.1514223 |
| _version_ | 1827809878218899456 |
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| author | J. A. Sepulveda-Toepfer Johannes Pichler Kathrin Fink Milica Sevo Sonja Wildburger Liesbeth Christiene Mudde-Boer Christopher Taus Geert Cornelius Mudde |
| author_facet | J. A. Sepulveda-Toepfer Johannes Pichler Kathrin Fink Milica Sevo Sonja Wildburger Liesbeth Christiene Mudde-Boer Christopher Taus Geert Cornelius Mudde |
| author_sort | J. A. Sepulveda-Toepfer |
| collection | DOAJ |
| description | The rational for designing dendritic cell (DC)-targeted immunotherapies is their central role in orchestrating immunity. Most studies addressing antigen-targeting to DCs for eliciting T cell responses have employed ex-vivo matured DCs derived from monocytes or myeloid DCs isolated from peripheral blood. More recently, also plasmacytoid DCs (pDCs) emerged as attractive targets that can be readily isolated and activated ex vivo. pDCs are known as key effectors of innate and adaptive immunity due to their exquisite ability to produce large amounts of type-1 interferons upon signaling via TLR7 or TLR9 intracellular receptor for viral RNA or bacterial DNA, respectively. In this study, we describe and characterize the immune modulating and targeting module of a composite human specific vaccine platform for active immunotherapy. This module, called warhead (WH), is composed of a single-chain variable fragment (scFv) and CpG-C type oligonucleotides (ODNs) that are covalently coupled. The scFv mediates specific binding to FcγRII/CD32 on APCs and internalization of the ODNs which stimulate TLR9-expressing B cells and pDCs. Furthermore, the scFv in the WH is extended with a five-time heptad repeat (EVSALEK) alpha helix which allows for a coiled-coil complex formation with any immunogen also extended with another five-time heptad (KVSALKE) repeat. WH elicits fast and robust pDC activation as evidenced by the release of interferon-α, TNF-α and IL-6. The WH thus takes advantage of the key features of human pDCs for immunostimulation and can be a versatile tool for antigen-specific vaccination with a variety of proteins or peptides. |
| first_indexed | 2024-03-11T22:45:22Z |
| format | Article |
| id | doaj.art-f87d43c506824261a3cbe986a3796ec3 |
| institution | Directory Open Access Journal |
| issn | 2164-5515 2164-554X |
| language | English |
| last_indexed | 2024-03-11T22:45:22Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Human Vaccines & Immunotherapeutics |
| spelling | doaj.art-f87d43c506824261a3cbe986a3796ec32023-09-22T08:38:23ZengTaylor & Francis GroupHuman Vaccines & Immunotherapeutics2164-55152164-554X2019-01-0115117918810.1080/21645515.2018.15142231514223TLR9-mediated activation of dendritic cells by CD32 targeting for the generation of highly immunostimulatory vaccinesJ. A. Sepulveda-Toepfer0Johannes Pichler1Kathrin Fink2Milica Sevo3Sonja Wildburger4Liesbeth Christiene Mudde-Boer5Christopher Taus6Geert Cornelius Mudde7S-TARget Therapeutics GmbHOncoQR ML GmbHOncoQR ML GmbHS-TARget Therapeutics GmbHS-TARget Therapeutics GmbHOncoQR ML GmbHOncoQR ML GmbHS-TARget Therapeutics GmbHThe rational for designing dendritic cell (DC)-targeted immunotherapies is their central role in orchestrating immunity. Most studies addressing antigen-targeting to DCs for eliciting T cell responses have employed ex-vivo matured DCs derived from monocytes or myeloid DCs isolated from peripheral blood. More recently, also plasmacytoid DCs (pDCs) emerged as attractive targets that can be readily isolated and activated ex vivo. pDCs are known as key effectors of innate and adaptive immunity due to their exquisite ability to produce large amounts of type-1 interferons upon signaling via TLR7 or TLR9 intracellular receptor for viral RNA or bacterial DNA, respectively. In this study, we describe and characterize the immune modulating and targeting module of a composite human specific vaccine platform for active immunotherapy. This module, called warhead (WH), is composed of a single-chain variable fragment (scFv) and CpG-C type oligonucleotides (ODNs) that are covalently coupled. The scFv mediates specific binding to FcγRII/CD32 on APCs and internalization of the ODNs which stimulate TLR9-expressing B cells and pDCs. Furthermore, the scFv in the WH is extended with a five-time heptad repeat (EVSALEK) alpha helix which allows for a coiled-coil complex formation with any immunogen also extended with another five-time heptad (KVSALKE) repeat. WH elicits fast and robust pDC activation as evidenced by the release of interferon-α, TNF-α and IL-6. The WH thus takes advantage of the key features of human pDCs for immunostimulation and can be a versatile tool for antigen-specific vaccination with a variety of proteins or peptides.http://dx.doi.org/10.1080/21645515.2018.1514223vaccineimmunotherapycpgcd32plasmacytoid dendritic cells |
| spellingShingle | J. A. Sepulveda-Toepfer Johannes Pichler Kathrin Fink Milica Sevo Sonja Wildburger Liesbeth Christiene Mudde-Boer Christopher Taus Geert Cornelius Mudde TLR9-mediated activation of dendritic cells by CD32 targeting for the generation of highly immunostimulatory vaccines Human Vaccines & Immunotherapeutics vaccine immunotherapy cpg cd32 plasmacytoid dendritic cells |
| title | TLR9-mediated activation of dendritic cells by CD32 targeting for the generation of highly immunostimulatory vaccines |
| title_full | TLR9-mediated activation of dendritic cells by CD32 targeting for the generation of highly immunostimulatory vaccines |
| title_fullStr | TLR9-mediated activation of dendritic cells by CD32 targeting for the generation of highly immunostimulatory vaccines |
| title_full_unstemmed | TLR9-mediated activation of dendritic cells by CD32 targeting for the generation of highly immunostimulatory vaccines |
| title_short | TLR9-mediated activation of dendritic cells by CD32 targeting for the generation of highly immunostimulatory vaccines |
| title_sort | tlr9 mediated activation of dendritic cells by cd32 targeting for the generation of highly immunostimulatory vaccines |
| topic | vaccine immunotherapy cpg cd32 plasmacytoid dendritic cells |
| url | http://dx.doi.org/10.1080/21645515.2018.1514223 |
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