Prolonged Circulation Half-life of Interferon γ Activity by Gene Delivery of Interferon γ–Serum Albumin Fusion Protein in Mice

Miyakawa, N; Nishikawa, Makiya; Takahashi, Yuki; Ando, Mitsuru; Misaka, Masayuki; Watanabe, Yoshihiko; Takakura, Yoshinobu

doi:10.1002/jps.22473

Cited by 24 publications

(13 citation statements)

References 27 publications

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“…These results were not observed in epithelial A549 cells, which surprisingly did not express the IFN-␥ receptor at the cell surface (data not shown). Interestingly, however, we were able to confirm the role of packaged A5 on virus replication in vivo after 48 h of IFN-␥ administration in mice, a period during which its biological activity remains stable (43).…”

Section: Discussionmentioning

confidence: 73%

Annexin V Incorporated into Influenza Virus Particles Inhibits Gamma Interferon Signaling and Promotes Viral Replication

Berri

Haffar

Lê

et al. 2014

J Virol

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During the budding process, influenza A viruses (IAVs) incorporate multiple host cell membrane proteins. However, for most of them, their significance in viral morphogenesis and infectivity remains unknown. We demonstrate here that the expression of annexin V (A5) is upregulated at the cell surface upon IAV infection and that a substantial proportion of the protein is present in lipid rafts, the site of virus budding. Western blotting and immunogold analysis of highly purified IAV particles showed the presence of A5 in the virion. Significantly, gamma interferon (IFN-␥)-induced Stat phosphorylation and IFN-␥-induced 10-kDa protein (IP-10) production in macrophage-derived THP-1 cells was inhibited by purified IAV particles. Disruption of the IFN-␥ signaling pathway was A5 dependent since downregulation of its expression or its blockage reversed the inhibition and resulted in decreased viral replication in vitro. The functional significance of these results was also observed in vivo. Thus, IAVs can subvert the IFN-␥ antiviral immune response by incorporating A5 into their envelope during the budding process. IMPORTANCEMany enveloped viruses, including influenza A viruses, bud from the plasma membrane of their host cells and incorporate cellular surface proteins into viral particles. However, for the vast majority of these proteins, only the observation of their incorporation has been reported. We demonstrate here that the host protein annexin V is specifically incorporated into influenza virus particles during the budding process. Importantly, we showed that packaged annexin V counteracted the antiviral activity of gamma interferon in vitro and in vivo. Thus, these results showed that annexin V incorporated in the viral envelope of influenza viruses allow viral escape from immune surveillance. Understanding the role of host incorporated protein into virions may reveal how enveloped RNA viruses hijack the host cell machinery for their own purposes.

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Section: Discussionmentioning

confidence: 73%

Annexin V Incorporated into Influenza Virus Particles Inhibits Gamma Interferon Signaling and Promotes Viral Replication

Berri

Haffar

Lê

et al. 2014

J Virol

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“…On the other hand, the use of type-I IFN has been poorly effective, largely due to toxic effects. To overcome the systemic sideeffects, several IFN delivery systems have been developed, such as the conjugation with polyethylene glycol (PEG) [13,19], gene delivery by albumin fusion protein [20], and microspheres for a constant release [21,22].…”

Section: Introductionmentioning

confidence: 99%

A site-selective hyaluronan-interferonα2a conjugate for the treatment of ovarian cancer

Montagner

Merlo

Carpanese

et al. 2016

Journal of Controlled Release

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While interferon alpha (IFNα) is used in several viral and cancer contexts, its efficacy against ovarian cancer (OC) is far from being incontrovertibly demonstrated and, more importantly, is hindered by heavy systemic side effects. To overcome these issues, here we propose a strategy that allows a targeted delivery of the cytokine, by conjugating IFNα2a with an aldehyde-modified form of hyaluronic acid (HA). The resulting HA-IFNα2a bioconjugate was biochemically and biologically characterized. The conjugation with HA did not substantially modified both the antiviral function and the anti-proliferative activity of the cytokine. Moreover, the induction of STAT1 phosphorylation and of a specific gene expression signature in different targets was retained. In vivo optical imaging biodistribution showed that the i.p.-injected HA-IFNα2a persisted into the peritoneal cavity longer than IFNα2a without being toxic for intraperitoneal organs, thus potentially enhancing the loco-regional therapeutic effect. Indeed, in OC xenograft mouse models bioconjugate significantly improved survival as compared to the free cytokine. Overall, HA-IFNα2a bioconjugate disclosed an improved anticancer efficacy, and can be envisaged as a promising loco-regional treatment for OC.

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“…Modification by engineering of large protein molecules is a common method to extend serum half‐life. The most common modifications are fusion with albumin or Fc, which significantly extended the half‐life of protein ligands, such as interferon gamma (γINF)‐fused with human serum albumin . PEGylation (polyethylene glycol conjugation) has a significant pharmacokinetic effect by slowing down clearance, however there seems to be some safety concerns regarding vacuolization in renal cells .…”

Section: Introductionmentioning

confidence: 99%

“…The most common modifications are fusion with albumin or Fc, which significantly extended the half-life of protein ligands, such as interferon gamma (γINF)-fused with human serum albumin. 21 PEGylation (polyethylene glycol conjugation) has a significant pharmacokinetic effect by slowing down clearance, however there seems to be some safety concerns regarding vacuolization in renal cells. 22,23 An additional modification approach is a site-specific glycosylation of protein molecules that improves pharmacokinetic (PK) property by increasing stability due to reduced protease sensitivity with bulky glycol moiety, which may reduce potential immunogenicity as well.…”

mentioning

confidence: 99%

Utility of Glycosylated TIMP3 molecules: Inhibition of MMPs and TACE to improve cardiac function in rat myocardial infarct model

Chintalgattu

Greenberg

Singh

et al. 2018

Pharmacology Res & Perspec

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Tissue Inhibitor of Metalloproteinase 3 (TIMP3) is a secreted protein that has a great utility to inhibit elevated metalloproteinase (MMP) activity in injured tissues including infarcted cardiac tissue, inflamed vessels, and joint cartilages. An imbalance between TIMP3 and active MMP levels in the local tissue area may cause worsening of disease progression. To counter balance elevated MMP levels, exogenous administration of TIMP3 appeared to be beneficial in preclinical studies. However, the current form of WT‐TIMP3 molecule has a limitation to be a therapeutic candidate due to low production yield, short plasma half‐life, injection site retention, and difficulty in delivery, etc. We have engineered TIMP3 molecules by adding extra glycosylation sites or fusing with albumin, Fc, and antibody to improve pharmacokinetic properties. In general, the C‐terminal fusion of TIMP3 improved expression and production in mammalian cells and extended half‐lives dramatically 5‐20 folds. Of note, a site‐specific glycosylation at K22S/F34N resulted in a higher level of expression and better cardiac function compared to other fusion proteins in the context of left ventricle ejection fraction (LVEF) changes in a rat myocardial infarction model. It appeared that cardiac efficacy depends on a high ECM binding affinity, in which K22S/F34N and N‐TIMP3 showed a higher binding to the ECM compared to other engineered molecules. In conclusion, we found that the ECM binding and sustained residence of injected TIMP3 molecules are important for cardiac tissue localization and inhibition of adverse remodeling activity.

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Prolonged Circulation Half-life of Interferon γ Activity by Gene Delivery of Interferon γ–Serum Albumin Fusion Protein in Mice

Cited by 24 publications

References 27 publications

Annexin V Incorporated into Influenza Virus Particles Inhibits Gamma Interferon Signaling and Promotes Viral Replication

Annexin V Incorporated into Influenza Virus Particles Inhibits Gamma Interferon Signaling and Promotes Viral Replication

A site-selective hyaluronan-interferonα2a conjugate for the treatment of ovarian cancer

Utility of Glycosylated TIMP3 molecules: Inhibition of MMPs and TACE to improve cardiac function in rat myocardial infarct model

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