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Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody.

Mailly L, Xiao F, Lupberger J, Wilson GK, Aubert P, Duong FH, Calabrese D, Leboeuf C, Fofana I, Thumann C, Bandiera S, Lütgehetmann M, Volz T, Davis C, Harris HJ, Mee CJ, Girardi E, Chane-Woon-Ming B, Ericsson M, Fletcher N, Bartenschlager R, Pessaux P, Vercauteren K, Meuleman P, Villa P, Kaderali L, Pfeffer S, Heim MH, Neunlist M, Zeisel MB, Dandri M, McKeating JA, Robinet E, Baumert TF - Nat. Biotechnol. (2015)

Bottom Line: Cell entry of HCV and other pathogens is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet.This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events.In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.

View Article: PubMed Central - PubMed

Affiliation: 1] Institut National de la Santé et de la Recherche Médicale, Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France. [2] Université de Strasbourg, Strasbourg, France.

ABSTRACT
Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer. Cell entry of HCV and other pathogens is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver-chimeric mouse model, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.

No MeSH data available.


Related in: MedlinePlus

Prevention and clearance of chronic HCV infection using a CLDN1-specific mAb in vivo(a, b) Prevention studies. Chimeric uPA-SCID mice received 500 μg CLDN1-specific (n=5) or control mAb (n=4) on days −1, 1 and 5 (arrows) of inoculation (star) with genotype 1b (a) or genotype 4 (b) HCV-containing serum. One infected mouse injected with control mAb died on day 26 (a, cross). (c-e) Treatment studies. Chimeric uPA-SCID mice were chronically infected with HCVcc Jc115 (genotype 2a/2a) (c), HCVcc VL-JFH117 (genotype 1b/2a) (d) or serum of genotype 2a (e). Twenty-four to 50 days following inoculation, the animals received 500 μg control (c, d, e; n=4, 3 and 4 respectively) or CLDN1-specific mAb (c, d, e; n=5, 5 and 6 respectively) each week (arrows) for 4 weeks. Two CLDN1-specific mAb treated mice were sacrificed following viral clearance for FISH studies (e). (f-j) Serum concentration of CLDN1-specific mAb from (a-e respectively) was determined by ELISA. Serum viral load (a-e) was quantified by the clinically licensed Abbott RealTime™ HCV assay. The horizontal dashed line indicates the limit of quantification (LOQ). (c, d, h, i) The viral load and antibody concentration of the mice exhibiting a relapse is indicated by a dashed line. Values of individual animals are shown.
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Figure 2: Prevention and clearance of chronic HCV infection using a CLDN1-specific mAb in vivo(a, b) Prevention studies. Chimeric uPA-SCID mice received 500 μg CLDN1-specific (n=5) or control mAb (n=4) on days −1, 1 and 5 (arrows) of inoculation (star) with genotype 1b (a) or genotype 4 (b) HCV-containing serum. One infected mouse injected with control mAb died on day 26 (a, cross). (c-e) Treatment studies. Chimeric uPA-SCID mice were chronically infected with HCVcc Jc115 (genotype 2a/2a) (c), HCVcc VL-JFH117 (genotype 1b/2a) (d) or serum of genotype 2a (e). Twenty-four to 50 days following inoculation, the animals received 500 μg control (c, d, e; n=4, 3 and 4 respectively) or CLDN1-specific mAb (c, d, e; n=5, 5 and 6 respectively) each week (arrows) for 4 weeks. Two CLDN1-specific mAb treated mice were sacrificed following viral clearance for FISH studies (e). (f-j) Serum concentration of CLDN1-specific mAb from (a-e respectively) was determined by ELISA. Serum viral load (a-e) was quantified by the clinically licensed Abbott RealTime™ HCV assay. The horizontal dashed line indicates the limit of quantification (LOQ). (c, d, h, i) The viral load and antibody concentration of the mice exhibiting a relapse is indicated by a dashed line. Values of individual animals are shown.

Mentions: To investigate the antiviral effect of this CLDN1-specific mAb, chimeric uPA-SCID mice received CLDN1-specific (n=5) or control isotype-matched irrelevant mAb (n=4) one day prior to inoculation, and 1 and 5 days post-infection with a primary HCV genotype 1b serum. The CLDN1-specific mAb provided a complete and sustained protection from infection as evidenced by undetectable HCV RNA in the sera for up to 6 weeks post-infection (Fig.2a, Supplementary Table 1). In contrast, all control mAb-treated mice became infected (Fig.2a). Similar results were observed following infection with a HCV of the difficult-to-treat genotype 4 (isolate ED4314, Fig.2b, Supplementary Table 1) demonstrating a significant level of anti-viral activity (p< 0.0002, pooled data from experiments of both genotypes, Mann-Whitney test). Pharmacokinetic studies showed that CLDN1-specific mAb levels declined rapidly and were undetectable 2 weeks after administration (Fig.2f-g). Collectively, these data show that short-term administration of a CLDN1-specific mAb prevents de novo HCV infection and suggests that it might be used to prevent HCV re-infection during liver transplantation.


Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody.

Mailly L, Xiao F, Lupberger J, Wilson GK, Aubert P, Duong FH, Calabrese D, Leboeuf C, Fofana I, Thumann C, Bandiera S, Lütgehetmann M, Volz T, Davis C, Harris HJ, Mee CJ, Girardi E, Chane-Woon-Ming B, Ericsson M, Fletcher N, Bartenschlager R, Pessaux P, Vercauteren K, Meuleman P, Villa P, Kaderali L, Pfeffer S, Heim MH, Neunlist M, Zeisel MB, Dandri M, McKeating JA, Robinet E, Baumert TF - Nat. Biotechnol. (2015)

Prevention and clearance of chronic HCV infection using a CLDN1-specific mAb in vivo(a, b) Prevention studies. Chimeric uPA-SCID mice received 500 μg CLDN1-specific (n=5) or control mAb (n=4) on days −1, 1 and 5 (arrows) of inoculation (star) with genotype 1b (a) or genotype 4 (b) HCV-containing serum. One infected mouse injected with control mAb died on day 26 (a, cross). (c-e) Treatment studies. Chimeric uPA-SCID mice were chronically infected with HCVcc Jc115 (genotype 2a/2a) (c), HCVcc VL-JFH117 (genotype 1b/2a) (d) or serum of genotype 2a (e). Twenty-four to 50 days following inoculation, the animals received 500 μg control (c, d, e; n=4, 3 and 4 respectively) or CLDN1-specific mAb (c, d, e; n=5, 5 and 6 respectively) each week (arrows) for 4 weeks. Two CLDN1-specific mAb treated mice were sacrificed following viral clearance for FISH studies (e). (f-j) Serum concentration of CLDN1-specific mAb from (a-e respectively) was determined by ELISA. Serum viral load (a-e) was quantified by the clinically licensed Abbott RealTime™ HCV assay. The horizontal dashed line indicates the limit of quantification (LOQ). (c, d, h, i) The viral load and antibody concentration of the mice exhibiting a relapse is indicated by a dashed line. Values of individual animals are shown.
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Related In: Results  -  Collection

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Figure 2: Prevention and clearance of chronic HCV infection using a CLDN1-specific mAb in vivo(a, b) Prevention studies. Chimeric uPA-SCID mice received 500 μg CLDN1-specific (n=5) or control mAb (n=4) on days −1, 1 and 5 (arrows) of inoculation (star) with genotype 1b (a) or genotype 4 (b) HCV-containing serum. One infected mouse injected with control mAb died on day 26 (a, cross). (c-e) Treatment studies. Chimeric uPA-SCID mice were chronically infected with HCVcc Jc115 (genotype 2a/2a) (c), HCVcc VL-JFH117 (genotype 1b/2a) (d) or serum of genotype 2a (e). Twenty-four to 50 days following inoculation, the animals received 500 μg control (c, d, e; n=4, 3 and 4 respectively) or CLDN1-specific mAb (c, d, e; n=5, 5 and 6 respectively) each week (arrows) for 4 weeks. Two CLDN1-specific mAb treated mice were sacrificed following viral clearance for FISH studies (e). (f-j) Serum concentration of CLDN1-specific mAb from (a-e respectively) was determined by ELISA. Serum viral load (a-e) was quantified by the clinically licensed Abbott RealTime™ HCV assay. The horizontal dashed line indicates the limit of quantification (LOQ). (c, d, h, i) The viral load and antibody concentration of the mice exhibiting a relapse is indicated by a dashed line. Values of individual animals are shown.
Mentions: To investigate the antiviral effect of this CLDN1-specific mAb, chimeric uPA-SCID mice received CLDN1-specific (n=5) or control isotype-matched irrelevant mAb (n=4) one day prior to inoculation, and 1 and 5 days post-infection with a primary HCV genotype 1b serum. The CLDN1-specific mAb provided a complete and sustained protection from infection as evidenced by undetectable HCV RNA in the sera for up to 6 weeks post-infection (Fig.2a, Supplementary Table 1). In contrast, all control mAb-treated mice became infected (Fig.2a). Similar results were observed following infection with a HCV of the difficult-to-treat genotype 4 (isolate ED4314, Fig.2b, Supplementary Table 1) demonstrating a significant level of anti-viral activity (p< 0.0002, pooled data from experiments of both genotypes, Mann-Whitney test). Pharmacokinetic studies showed that CLDN1-specific mAb levels declined rapidly and were undetectable 2 weeks after administration (Fig.2f-g). Collectively, these data show that short-term administration of a CLDN1-specific mAb prevents de novo HCV infection and suggests that it might be used to prevent HCV re-infection during liver transplantation.

Bottom Line: Cell entry of HCV and other pathogens is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet.This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events.In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.

View Article: PubMed Central - PubMed

Affiliation: 1] Institut National de la Santé et de la Recherche Médicale, Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France. [2] Université de Strasbourg, Strasbourg, France.

ABSTRACT
Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer. Cell entry of HCV and other pathogens is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver-chimeric mouse model, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.

No MeSH data available.


Related in: MedlinePlus