Novel human SR-BI antibodies prevent infection and dissemination of HCV in vitro and in humanized mice

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• 作者：Krzysztof Lacek¹ ; ^&dagger ; ; Koen Vercauteren² ; ^&dagger ; ; Katarzyna Grzyb³ ; Mariarosaria Naddeo¹ ; Lieven Verhoye² ; Marek Patryk S艂owikowski¹ ; Samira Fafi-Kremer⁴ ; Arvind H. Patel⁵ ; Thomas F. Baumert⁴ ; Antonella Folgori¹ ; Geert Leroux-Roels² ; Riccardo Cortese¹ ; Philip Meuleman² ; ^{Philip.meuleman@ugent.be} ; Alfredo Nicosia¹ ; ⁶ ; ^{nicosia@ceinge.unina.it}
• 关键词：HCV ; hepatitis C virus ; mAbs ; monoclonal antibodies ; SR-BI/Cla1 ; scavenger receptor class B type I ; uPA ; urokinase-type plasminogen activator ; SCID ; severe combined immunodeficient ; LT ; liver transplantation ; FDA ; Food and Drug Administration ; E1/E2 ; enve
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：July, 2012
• 卷：57
• 期：1
• 页码：17-23
• 文件大小：1072 K

摘要

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Background & Aims

Hepatitis C virus (HCV)-induced end-stage liver disease is currently the major indication for liver transplantation in the Western world. After transplantation, the donor liver almost inevitably becomes infected by the circulating virus and disease progression is accelerated in immune suppressed transplant patients. The current standard therapy, based on pegylated interferon and ribavirin, induces severe side effects and is often ineffective in this population. Therefore, new strategies to prevent graft re-infection are urgently needed. We have previously shown that monoclonal antibodies (mAbs) against the HCV co-receptor scavenger receptor class B type I (SR-BI/Cla1) inhibit infection by different HCV genotypes in cell culture.

Methods

Using phage display libraries, we have generated a large set of novel human mAbs against SR-BI and evaluated their effectiveness in preventing HCV infection and direct cell-to-cell spread in vitro and in vivo using uPA-SCID mice with a humanized liver.

Results

Eleven human monoclonal antibodies were generated that specifically recognize SR-BI. Two antibodies, mAb8 and mAb151, displayed the highest binding and inhibitory properties and also interfered with direct cell-to-cell spread in vitro. Studies in humanized mice showed that both antibodies were capable of preventing HCV infection and could block intrahepatic spread and virus amplification when administered 3 days after infection. Interestingly, anti-SR-BI therapy was effective against an HCV variant that escaped the control of the adaptive immune response in a liver transplant patient.

Conclusions

The anti-SR-BI mAbs generated in this study may represent novel therapeutic tools to prevent HCV re-infection of liver allografts.