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Zifu Zhong
Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Heidestraat 19, 9820 Merelbeke, Belgium

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Journal article
Published: 20 January 2021 in Molecular Therapy
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Synthetic mRNAs are an appealing platform with multiple biomedical applications ranging from protein replacement therapy to vaccination. In comparison with conventional mRNA, synthetic self-amplifying mRNAs (sa-mRNAs) are gaining interest because of their higher and longer-lasting expression. However, sa-mRNAs also elicit an innate immune response, which may complicate their clinical application. Approaches to reduce the innate immunity of sa-mRNAs have not been studied in detail. Here we investigated, in vivo, the effect of several innate immune inhibitors and a novel cellulose-based mRNA purification approach on the type I interferon (IFN) response and the translation and vaccination efficacy of our formerly developed sa-mRNA vaccine against Zika virus. Among the investigated inhibitors, we found that corticosteroids and especially topical application of clobetasol at the sa-mRNA injection site was the most efficient in suppressing the type I IFN response and increasing the translation of sa-mRNA. However, clobetasol prevented formation of antibodies against sa-mRNA-encoded antigens and should therefore be avoided in a vaccination context. Residual dsRNA by-products of the in vitro transcription reaction are known inducers of immediate type I IFN responses. We additionally demonstrate a drastic reduction of these dsRNA by-products upon cellulose-based purification, reducing the innate immune response and improving sa-mRNA vaccination efficacy.

ACS Style

Zifu Zhong; Séan McCafferty; Lisa Opsomer; Haixiu Wang; Hanne Huysmans; Joyca De Temmerman; Stefan Lienenklaus; João Paulo Portela Catani; Francis Combes; Niek N. Sanders. Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs. Molecular Therapy 2021, 29, 1370 -1381.

AMA Style

Zifu Zhong, Séan McCafferty, Lisa Opsomer, Haixiu Wang, Hanne Huysmans, Joyca De Temmerman, Stefan Lienenklaus, João Paulo Portela Catani, Francis Combes, Niek N. Sanders. Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs. Molecular Therapy. 2021; 29 (4):1370-1381.

Chicago/Turabian Style

Zifu Zhong; Séan McCafferty; Lisa Opsomer; Haixiu Wang; Hanne Huysmans; Joyca De Temmerman; Stefan Lienenklaus; João Paulo Portela Catani; Francis Combes; Niek N. Sanders. 2021. "Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs." Molecular Therapy 29, no. 4: 1370-1381.

Preprint content
Published: 27 August 2020
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Synthetic mRNAs are an appealing therapeutic platform with multiple biomedical applications ranging from protein replacement therapy to vaccination. In comparison to conventional mRNA, synthetic self-amplifying mRNAs (sa-mRNAs) are gaining increased interest due to their higher and longer-lasting expression. However, sa-mRNAs also elicit an innate immune response, which may complicate the clinical translation of this platform. Approaches to reduce the innate immunity of sa-mRNAs have not been studied in detail. In this work we investigated the effect of several innate immune inhibitors and a novel cellulose-based mRNA purification approach on the type I interferon (IFN) response, translation and vaccination efficacy of our formerly developed sa-mRNA vaccine against Zika virus. Among the investigated inhibitors, we found that topical application of clobetasol at the sa-mRNA injection site was the most efficient in suppressing the type I IFN response and increasing the translation of sa-mRNA. However, clobetasol prevented the formation of antibodies against sa-mRNA encoded antigens and should therefore be avoided in a vaccination context. Residual dsRNA by-products of the in vitro transcription reaction are known inducers of immediate type I IFN responses. We additionally demonstrate drastic reduction of these dsRNA by-products upon cellulose-based purification, consequently reducing the innate immune response and improving sa-mRNA vaccination efficacy.

ACS Style

Zifu Zhong; Séan Mc Cafferty; Lisa Opsomer; Haixiu Wang; Hanne Huysmans; Joyca De Temmerman; Stefan Lienenklaus; João Paulo Portela Catani; Francis Combes; Niek N. Sanders. Corticosteroids and cellulose purification improve respectively the in vivo translation and vaccination efficacy of self-amplifying mRNAs. 2020, 1 .

AMA Style

Zifu Zhong, Séan Mc Cafferty, Lisa Opsomer, Haixiu Wang, Hanne Huysmans, Joyca De Temmerman, Stefan Lienenklaus, João Paulo Portela Catani, Francis Combes, Niek N. Sanders. Corticosteroids and cellulose purification improve respectively the in vivo translation and vaccination efficacy of self-amplifying mRNAs. . 2020; ():1.

Chicago/Turabian Style

Zifu Zhong; Séan Mc Cafferty; Lisa Opsomer; Haixiu Wang; Hanne Huysmans; Joyca De Temmerman; Stefan Lienenklaus; João Paulo Portela Catani; Francis Combes; Niek N. Sanders. 2020. "Corticosteroids and cellulose purification improve respectively the in vivo translation and vaccination efficacy of self-amplifying mRNAs." , no. : 1.

Minireview
Published: 14 July 2020 in Angewandte Chemie International Edition
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The current COVID‐19 pandemic has a tremendous impact on daily life world‐wide. Despite the ability to dampen the spread of SARS‐CoV‐2, the causative agent of the diseases, through restrictive interventions, it is believed that only effective vaccines will provide sufficient control over the disease and revert societal live back to normal. At present, a double‐digit number of efforts are devoted to the development of a vaccine against COVID‐19. Here, we provide an overview of these (pre)clinical efforts and provide background information on the technologies behind these vaccines. In addition, we discuss potential hurdles that need to be addressed prior to mass scale clinical translation of successful vaccine candidates.

ACS Style

Tingting Ye; Zifu Zhong; Adolfo García‐Sastre; Michael Schotsaert; Bruno G. De Geest. Current Status of COVID‐19 (Pre)Clinical Vaccine Development. Angewandte Chemie International Edition 2020, 59, 18885 -18897.

AMA Style

Tingting Ye, Zifu Zhong, Adolfo García‐Sastre, Michael Schotsaert, Bruno G. De Geest. Current Status of COVID‐19 (Pre)Clinical Vaccine Development. Angewandte Chemie International Edition. 2020; 59 (43):18885-18897.

Chicago/Turabian Style

Tingting Ye; Zifu Zhong; Adolfo García‐Sastre; Michael Schotsaert; Bruno G. De Geest. 2020. "Current Status of COVID‐19 (Pre)Clinical Vaccine Development." Angewandte Chemie International Edition 59, no. 43: 18885-18897.

Research article
Published: 11 June 2020 in Journal of the American Chemical Society
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Synthetic immune-stimulatory drugs such as agonists of the Toll-like receptors (TLR) 7/8 are potent activators of antigen-presenting cells (APCs), however, they also induce severe side effects due to leakage from the site of injection into systemic circulation. Here, we report on the design and synthesis of an amphiphilic polymer-prodrug conjugate of an imidazoquinoline TLR7/8 agonist that in aqueous medium forms vesicular structures of 200 nm. The conjugate contains an endosomal enzyme-responsive linker enabling degradation of the vesicles and release of the TLR7/8 agonist in native form after endocytosis, which results in high in vitro TLR agonist activity. In a mouse model, locally administered vesicles provoke significantly more potent and long-lasting immune stimulation in terms of interferon expression at the injection site and in draining lymphoid tissue compared to a nonamphiphilic control and the native TLR agonist. Moreover, the vesicles induce robust activation of dendritic cells in the draining lymph node in vivo.

ACS Style

Bi Wang; Simon Van Herck; Yong Chen; Xiangyang Bai; Zifu Zhong; Kim De Swarte; Bart N. Lambrecht; Niek N. Sanders; Stefan Lienenklaus; Hans W. Scheeren; Sunil A. David; Fabian Kiessling; Twan Lammers; Bruno G. De Geest; Yang Shi. Potent and Prolonged Innate Immune Activation by Enzyme-Responsive Imidazoquinoline TLR7/8 Agonist Prodrug Vesicles. Journal of the American Chemical Society 2020, 142, 12133 -12139.

AMA Style

Bi Wang, Simon Van Herck, Yong Chen, Xiangyang Bai, Zifu Zhong, Kim De Swarte, Bart N. Lambrecht, Niek N. Sanders, Stefan Lienenklaus, Hans W. Scheeren, Sunil A. David, Fabian Kiessling, Twan Lammers, Bruno G. De Geest, Yang Shi. Potent and Prolonged Innate Immune Activation by Enzyme-Responsive Imidazoquinoline TLR7/8 Agonist Prodrug Vesicles. Journal of the American Chemical Society. 2020; 142 (28):12133-12139.

Chicago/Turabian Style

Bi Wang; Simon Van Herck; Yong Chen; Xiangyang Bai; Zifu Zhong; Kim De Swarte; Bart N. Lambrecht; Niek N. Sanders; Stefan Lienenklaus; Hans W. Scheeren; Sunil A. David; Fabian Kiessling; Twan Lammers; Bruno G. De Geest; Yang Shi. 2020. "Potent and Prolonged Innate Immune Activation by Enzyme-Responsive Imidazoquinoline TLR7/8 Agonist Prodrug Vesicles." Journal of the American Chemical Society 142, no. 28: 12133-12139.

Journal article
Published: 21 October 2019 in Angewandte Chemie International Edition
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Uncontrolled systemic inflammatory immune triggering has hampered the clinical translation of several classes of small-molecule immunomodulators, such as imidazoquinoline TLR7/8 agonists for vaccine design and cancer immunotherapy. By taking advantage of the inherent serum-protein-binding property of lipid motifs and their tendency to accumulate in lymphoid tissue, we designed amphiphilic lipid-polymer conjugates that suppress systemic inflammation but provoke potent lymph-node immune activation. This work provides a rational basis for the design of lipid-polymer amphiphiles for optimized lymphoid targeting.

ACS Style

Jana De Vrieze; Benoit Louage; Kim Deswarte; Zifu Zhong; Ruben De Coen; Simon Van Herck; Lutz Nuhn; Camilla Kaas Frich; Alexander Zelikin; Stefan Lienenklaus; Niek N. Sanders; Bart N. Lambrecht; Sunil A. David; Bruno G. De Geest. Potent Lymphatic Translocation and Spatial Control Over Innate Immune Activation by Polymer–Lipid Amphiphile Conjugates of Small‐Molecule TLR7/8 Agonists. Angewandte Chemie International Edition 2019, 58, 15390 -15395.

AMA Style

Jana De Vrieze, Benoit Louage, Kim Deswarte, Zifu Zhong, Ruben De Coen, Simon Van Herck, Lutz Nuhn, Camilla Kaas Frich, Alexander Zelikin, Stefan Lienenklaus, Niek N. Sanders, Bart N. Lambrecht, Sunil A. David, Bruno G. De Geest. Potent Lymphatic Translocation and Spatial Control Over Innate Immune Activation by Polymer–Lipid Amphiphile Conjugates of Small‐Molecule TLR7/8 Agonists. Angewandte Chemie International Edition. 2019; 58 (43):15390-15395.

Chicago/Turabian Style

Jana De Vrieze; Benoit Louage; Kim Deswarte; Zifu Zhong; Ruben De Coen; Simon Van Herck; Lutz Nuhn; Camilla Kaas Frich; Alexander Zelikin; Stefan Lienenklaus; Niek N. Sanders; Bart N. Lambrecht; Sunil A. David; Bruno G. De Geest. 2019. "Potent Lymphatic Translocation and Spatial Control Over Innate Immune Activation by Polymer–Lipid Amphiphile Conjugates of Small‐Molecule TLR7/8 Agonists." Angewandte Chemie International Edition 58, no. 43: 15390-15395.

Journal article
Published: 23 August 2019 in Vaccines
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To combat emerging infectious diseases like Zika virus (ZIKV), synthetic messenger RNAs (mRNAs) encoding viral antigens are very attractive as they allow a rapid, generic, and flexible production of vaccines. In this work, we engineered a self-replicating mRNA (sr-mRNA) vaccine encoding the pre-membrane and envelope (prM-E) glycoproteins of ZIKV. Intradermal electroporation of as few as 1 µg of this mRNA-based ZIKV vaccine induced potent humoral and cellular immune responses in BALB/c and especially IFNAR1-/- C57BL/6 mice, resulting in a complete protection of the latter mice against ZIKV infection. In wild-type C57BL/6 mice, the vaccine resulted in very low seroconversion rates and antibody titers. The potency of the vaccine was inversely related to the dose of mRNA used in wild-type BALB/c or C57BL/6 mice, as robust type I interferon (IFN) response was determined in a reporter mice model (IFN-β+/Δβ-luc). We further investigated the inability of the sr-prM-E-mRNA ZIKV vaccine to raise antibodies in wild-type C57BL/6 mice and found indications that type I IFNs elicited by this naked sr-mRNA vaccine might directly impede the induction of a robust humoral response. Therefore, we assume that the efficacy of sr-mRNA vaccines after intradermal electroporation might be increased by strategies that temper their inherent innate immunogenicity.

ACS Style

Zifu Zhong; João Paulo Portela Catani; Séan Mc Cafferty; Liesbeth Couck; Wim Van Den Broeck; Nina Gorlé; Roosmarijn E. Vandenbroucke; Bert Devriendt; Sebastian Ulbert; Lieselotte Cnops; Johan Michels; Kevin K. Ariën; Niek N. Sanders. Immunogenicity and Protection Efficacy of a Naked Self-Replicating mRNA-Based Zika Virus Vaccine. Vaccines 2019, 7, 96 .

AMA Style

Zifu Zhong, João Paulo Portela Catani, Séan Mc Cafferty, Liesbeth Couck, Wim Van Den Broeck, Nina Gorlé, Roosmarijn E. Vandenbroucke, Bert Devriendt, Sebastian Ulbert, Lieselotte Cnops, Johan Michels, Kevin K. Ariën, Niek N. Sanders. Immunogenicity and Protection Efficacy of a Naked Self-Replicating mRNA-Based Zika Virus Vaccine. Vaccines. 2019; 7 (3):96.

Chicago/Turabian Style

Zifu Zhong; João Paulo Portela Catani; Séan Mc Cafferty; Liesbeth Couck; Wim Van Den Broeck; Nina Gorlé; Roosmarijn E. Vandenbroucke; Bert Devriendt; Sebastian Ulbert; Lieselotte Cnops; Johan Michels; Kevin K. Ariën; Niek N. Sanders. 2019. "Immunogenicity and Protection Efficacy of a Naked Self-Replicating mRNA-Based Zika Virus Vaccine." Vaccines 7, no. 3: 96.

Original article
Published: 07 August 2019 in Molecular Therapy - Nucleic Acids
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In this work, we studied the expression kinetics and innate immune response of a self-amplifying mRNA (sa-RNA) after electroporation and lipid-nanoparticle (LNP)-mediated delivery in the skin of mice. Intradermal electroporation of the sa-RNA resulted in a plateau-shaped expression, with the plateau between day 3 and day 10. The overall protein expression of sa-RNA was significantly higher than that obtained after electroporation of plasmid DNA (pDNA) or non-replication mRNAs. Moreover, using IFN-β reporter mice, we elucidated that intradermal electroporation of sa-RNA induced a short-lived moderate innate immune response, which did not affect the expression of the sa-RNA. A completely different expression profile and innate immune response were observed when LNPs were used. The expression peaked 24 h after intradermal injection of sa-RNA-LNPs and subsequently showed a sharp drop. This drop might be explained by a translational blockage caused by the strong innate immune response that we observed in IFN-β reporter mice shortly (4 h) after intradermal injection of sa-RNA-LNPs. A final interesting observation was the capacity of sa-RNA-LNPs to transfect the draining lymph nodes after intradermal injection.

ACS Style

Hanne Huysmans; Zifu Zhong; Joyca De Temmerman; Barbara L. Mui; Ying K. Tam; Séan Mc Cafferty; Arlieke Gitsels; Daisy Vanrompay; Niek N. Sanders. Expression Kinetics and Innate Immune Response after Electroporation and LNP-Mediated Delivery of a Self-Amplifying mRNA in the Skin. Molecular Therapy - Nucleic Acids 2019, 17, 867 -878.

AMA Style

Hanne Huysmans, Zifu Zhong, Joyca De Temmerman, Barbara L. Mui, Ying K. Tam, Séan Mc Cafferty, Arlieke Gitsels, Daisy Vanrompay, Niek N. Sanders. Expression Kinetics and Innate Immune Response after Electroporation and LNP-Mediated Delivery of a Self-Amplifying mRNA in the Skin. Molecular Therapy - Nucleic Acids. 2019; 17 ():867-878.

Chicago/Turabian Style

Hanne Huysmans; Zifu Zhong; Joyca De Temmerman; Barbara L. Mui; Ying K. Tam; Séan Mc Cafferty; Arlieke Gitsels; Daisy Vanrompay; Niek N. Sanders. 2019. "Expression Kinetics and Innate Immune Response after Electroporation and LNP-Mediated Delivery of a Self-Amplifying mRNA in the Skin." Molecular Therapy - Nucleic Acids 17, no. : 867-878.

Journal article
Published: 27 June 2019 in Molecular Therapy - Nucleic Acids
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Local administration of naked self-replicating mRNA (sr-mRNA) in the skin or muscle using electroporation is effective but hampered by low repeatability. In this manuscript, we demonstrated that intradermal electroporation of sr-mRNA in combination with a protein-based RNase inhibitor increased the expression efficiency, success rate, and repeatability of the data. The RNase inhibitor should be added just before administration because storage of the inhibitor together with the sr-mRNA at −80°C resulted in a partial loss of the beneficial effect. Furthermore, the location of intradermal electroporation also had a major effect on the expression of the sr-mRNA, with the highest and longest expression observed at the tail base of the mice. In contrast with previous work, we did not observe a beneficial effect of calcium ions on the efficacy of naked sr-mRNA after intradermal injection. Finally, another important finding was that the traditional representation of in vivo bioluminescence data as means in logarithmic graphs can mask highly variable data. A more truthful representation can be obtained by showing the individual data points or by displaying median values in combination with interquartile ranges. In conclusion, intradermal sr-mRNA electroporation can be improved by adding an RNase inhibitor and injecting at the tail base.

ACS Style

Hanne Huysmans; Joyca De Temmerman; Zifu Zhong; Sean Mc Cafferty; Francis Combes; Freddy Haesebrouck; Niek N. Sanders. Improving the Repeatability and Efficacy of Intradermal Electroporated Self-Replicating mRNA. Molecular Therapy - Nucleic Acids 2019, 17, 388 -395.

AMA Style

Hanne Huysmans, Joyca De Temmerman, Zifu Zhong, Sean Mc Cafferty, Francis Combes, Freddy Haesebrouck, Niek N. Sanders. Improving the Repeatability and Efficacy of Intradermal Electroporated Self-Replicating mRNA. Molecular Therapy - Nucleic Acids. 2019; 17 ():388-395.

Chicago/Turabian Style

Hanne Huysmans; Joyca De Temmerman; Zifu Zhong; Sean Mc Cafferty; Francis Combes; Freddy Haesebrouck; Niek N. Sanders. 2019. "Improving the Repeatability and Efficacy of Intradermal Electroporated Self-Replicating mRNA." Molecular Therapy - Nucleic Acids 17, no. : 388-395.

Review
Published: 08 January 2019 in Toxins
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Enterotoxigenic Escherichia coli (ETEC) are an important diarrhea-causing pathogen and are regarded as a global threat for humans and farm animals. ETEC possess several virulence factors to infect its host, including colonization factors and enterotoxins. Production of heat-stable enterotoxins (STs) by most ETEC plays an essential role in triggering diarrhea and ETEC pathogenesis. In this review, we summarize the heat-stable enterotoxins of ETEC strains from different species as well as the molecular mechanisms used by these heat-stable enterotoxins to trigger diarrhea. As recently described, intestinal epithelial cells are important modulators of the intestinal immune system. Thus, we also discuss the impact of the heat-stable enterotoxins on this role of the intestinal epithelium and how these enterotoxins might affect intestinal immune cells. Finally, the latest developments in vaccination strategies to protect against infections with ST secreting ETEC strains are discussed. This review might inform and guide future research on heat-stable enterotoxins to further unravel their molecular pathogenesis, as well as to accelerate vaccine design.

ACS Style

Haixiu Wang; Zifu Zhong; Yu Luo; Eric Cox; Bert Devriendt. Heat-Stable Enterotoxins of Enterotoxigenic Escherichia coli and Their Impact on Host Immunity. Toxins 2019, 11, 24 .

AMA Style

Haixiu Wang, Zifu Zhong, Yu Luo, Eric Cox, Bert Devriendt. Heat-Stable Enterotoxins of Enterotoxigenic Escherichia coli and Their Impact on Host Immunity. Toxins. 2019; 11 (1):24.

Chicago/Turabian Style

Haixiu Wang; Zifu Zhong; Yu Luo; Eric Cox; Bert Devriendt. 2019. "Heat-Stable Enterotoxins of Enterotoxigenic Escherichia coli and Their Impact on Host Immunity." Toxins 11, no. 1: 24.

Review article
Published: 23 November 2018 in Nano Today
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Messenger RNA based therapeutics have the potential to cause a big revolution in medicine as they can facilitate personalized medicines and allow patients to produce their own therapeutic proteins without the current purification, solubility and inappropriate glycosylation issues associated with recombinant therapeutic proteins. Moreover, a generic and much cheaper production process can be used for mRNA therapeutics as the physicochemical properties of mRNA are independent of its sequence. Furthermore, mRNA vaccines will allow us to respond much quicker to epidemic outbreaks of dangerous infectious diseases as their production is much faster and more flexible than the production of the current vaccines. In the past, the in vivo delivery of mRNA therapeutics was considered as a major bottleneck. However, very recently it has been demonstrated that in vivo delivery issues like low cellular uptake and in vivo degradation by nucleases can be overcome by formulating the therapeutic mRNA into nanoparticles. In this review, we describe the different synthetic mRNA platforms, their production and purification, strategies to tackle the inherent innate immunogenicity of synthetic mRNA, the recent progress in the development of nanoformulations for the in vivo delivery of mRNA, as well as the efficacy and safety of mRNA therapeutics in recent clinical trials.

ACS Style

Zifu Zhong; Séan Mc Cafferty; Francis Combes; Hanne Huysmans; Joyca De Temmerman; Arlieke Gitsels; Daisy Vanrompay; João Portela Catani; Niek N. Sanders. mRNA therapeutics deliver a hopeful message. Nano Today 2018, 23, 16 -39.

AMA Style

Zifu Zhong, Séan Mc Cafferty, Francis Combes, Hanne Huysmans, Joyca De Temmerman, Arlieke Gitsels, Daisy Vanrompay, João Portela Catani, Niek N. Sanders. mRNA therapeutics deliver a hopeful message. Nano Today. 2018; 23 ():16-39.

Chicago/Turabian Style

Zifu Zhong; Séan Mc Cafferty; Francis Combes; Hanne Huysmans; Joyca De Temmerman; Arlieke Gitsels; Daisy Vanrompay; João Portela Catani; Niek N. Sanders. 2018. "mRNA therapeutics deliver a hopeful message." Nano Today 23, no. : 16-39.

Research article
Published: 02 October 2018 in Journal of the American Chemical Society
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Small molecule immuno-modulators such as agonists of Toll like receptors are attractive compounds to stimulate innate immune cells towards potent anti-viral and anti-tumor responses. However, small molecules rapidly enter sys-temic circulation and cause ‘wasted inflammation’. Hence, synthetic strategies to confine their radius of action to lymphoid tissue are of great relevance, to both enhance their efficacy and concomitantly limit toxicity. Here we demonstrate that covalent conjugation of a small molecule TLR7/8 agonist immunomodulatory to a micelle-forming amphiphilic block copolymer greatly alters the pharmacokinetic profile, resulting in highly efficient lymphatic deliv-ery. Moreover, we designed amphiphilic block copolymers in such way to form thermodynamically stable micelles through pi-pi stacking between aromatic moieties, and engineer the block copolymers to undergo an irreversible am-phiphilic to hydrophilic transition in response to the acidic endosomal pH.

ACS Style

Simon Van Herck; Kim Deswarte; Lutz Nuhn; Zifu Zhong; Joao Paulo Portela Catani; Yupeng Li; Niek N. Sanders; Stefan Lienenklaus; Stefaan De Koker; Bart N. Lambrecht; Sunil A. David; Bruno G. De Geest. Lymph-Node-Targeted Immune Activation by Engineered Block Copolymer Amphiphiles–TLR7/8 Agonist Conjugates. Journal of the American Chemical Society 2018, 140, 14300 -14307.

AMA Style

Simon Van Herck, Kim Deswarte, Lutz Nuhn, Zifu Zhong, Joao Paulo Portela Catani, Yupeng Li, Niek N. Sanders, Stefan Lienenklaus, Stefaan De Koker, Bart N. Lambrecht, Sunil A. David, Bruno G. De Geest. Lymph-Node-Targeted Immune Activation by Engineered Block Copolymer Amphiphiles–TLR7/8 Agonist Conjugates. Journal of the American Chemical Society. 2018; 140 (43):14300-14307.

Chicago/Turabian Style

Simon Van Herck; Kim Deswarte; Lutz Nuhn; Zifu Zhong; Joao Paulo Portela Catani; Yupeng Li; Niek N. Sanders; Stefan Lienenklaus; Stefaan De Koker; Bart N. Lambrecht; Sunil A. David; Bruno G. De Geest. 2018. "Lymph-Node-Targeted Immune Activation by Engineered Block Copolymer Amphiphiles–TLR7/8 Agonist Conjugates." Journal of the American Chemical Society 140, no. 43: 14300-14307.

Communication
Published: 01 October 2018 in Advanced Materials
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Localized therapeutic modalities that subvert the tumor microenvironment from immune‐suppressive to pro‐immunogenic can elicit systemic antitumor immune responses that induce regression of directly treated as well as nontreated distal tumors. A key toward generating robust antitumor T cell responses is the activation of dendritic cells (DCs) in the tumor microenvironment. Treatment with agonists triggering various pattern recognition receptors is very efficient to activate DCs, yet suffers from the induction of serious immune‐related adverse effects, which is closely linked to their unfavorable PK/PD profile causing systemic immune activation and cytokine release. Here, it is reported that nanoparticle conjugation of a highly potent TLR7/8 agonist restricts immune activation to the tumor bed and its sentinel lymph nodes without hampering therapeutic antitumor efficacy. On a mechanistic level, it is confirmed that localized treatment with a nanoparticle‐conjugated TLR7/8 agonist leads to potent activation of DCs in the sentinel lymph nodes and promotes proliferation of tumor antigen‐specific CD8 T cells. Furthermore, therapeutic improvement upon combination with anti‐PDL1 checkpoint inhibition and Flt3L, a growth factor that expands and mobilizes DCs from the bone marrow, is demonstrated. The findings provide a rational base for localized tumor engineering by nanomedicine strategies that provide spatial control over immune‐activation.

ACS Style

Lutz Nuhn; Stefaan De Koker; Sandra Van Lint; Zifu Zhong; João Portela Catani; Francis Combes; Kim Deswarte; Yupeng Li; Bart N. Lambrecht; Stefan Lienenklaus; Niek N. Sanders; Sunil A. David; Jan Tavernier; Bruno G. De Geest. Nanoparticle-Conjugate TLR7/8 Agonist Localized Immunotherapy Provokes Safe Antitumoral Responses. Advanced Materials 2018, 30, e1803397 .

AMA Style

Lutz Nuhn, Stefaan De Koker, Sandra Van Lint, Zifu Zhong, João Portela Catani, Francis Combes, Kim Deswarte, Yupeng Li, Bart N. Lambrecht, Stefan Lienenklaus, Niek N. Sanders, Sunil A. David, Jan Tavernier, Bruno G. De Geest. Nanoparticle-Conjugate TLR7/8 Agonist Localized Immunotherapy Provokes Safe Antitumoral Responses. Advanced Materials. 2018; 30 (45):e1803397.

Chicago/Turabian Style

Lutz Nuhn; Stefaan De Koker; Sandra Van Lint; Zifu Zhong; João Portela Catani; Francis Combes; Kim Deswarte; Yupeng Li; Bart N. Lambrecht; Stefan Lienenklaus; Niek N. Sanders; Sunil A. David; Jan Tavernier; Bruno G. De Geest. 2018. "Nanoparticle-Conjugate TLR7/8 Agonist Localized Immunotherapy Provokes Safe Antitumoral Responses." Advanced Materials 30, no. 45: e1803397.

Journal article
Published: 01 October 2015 in Gene
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Viperin is well known as one of the interferon-stimulated genes involved in innate immunity. Recent studies showed that this gene is mainly responsible for antiviral response to a large variety of viral infections. In this study, we successfully cloned and characterized the complete coding sequence of duck viperin gene. The duck viperin gene encodes 363 amino acids (aa) and is highly similar to viperins from other species. Moreover, secondary and 3D structures were predicted, and these structures showed two main domains, one signal peptide, and one radical S-adenosyl methionine (SAM) domain. Additionally, the duck viperin expression was analyzed in vitro and in vivo, and analysis results indicated that the duck viperin can be strongly up-regulated by poly(I:C) and Newcastle disease virus in primary duck embryo fibroblast cells. Results also demonstrated that Newcastle disease virus significantly induced duck viperin expression in the spleen, kidneys, liver, brain, and blood. Our findings will contribute to future studies on the detailed functions and potential underlying mechanisms of this novel protein in innate immunity.

ACS Style

Zifu Zhong; Yanhong Ji; Yuguang Fu; Bin Liu; Qiyun Zhu. Molecular characterization and expression analysis of the duck viperin gene. Gene 2015, 570, 100 -107.

AMA Style

Zifu Zhong, Yanhong Ji, Yuguang Fu, Bin Liu, Qiyun Zhu. Molecular characterization and expression analysis of the duck viperin gene. Gene. 2015; 570 (1):100-107.

Chicago/Turabian Style

Zifu Zhong; Yanhong Ji; Yuguang Fu; Bin Liu; Qiyun Zhu. 2015. "Molecular characterization and expression analysis of the duck viperin gene." Gene 570, no. 1: 100-107.