A Human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo

Abstract

End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the Western world. However, immediate re-infection of the grafted donor liver by circulating virus is inevitable and progresses much faster than the original disease. Standard antiviral therapy is not well tolerated and usually ineffective in liver transplant patients while anti-HCV immunotherapy is hampered by the extreme genetic diversity of the virus and its ability to spread via cell-cell contacts. We have generated a human monoclonal antibody against SR-BI, mAb16-71, that can efficiently prevent infection of Huh-7.5 hepatoma cells and primary hepatocytes by cell-culture-derived HCV (HCVcc). Using an Huh7.5 co-culture system we demonstrated that mAb16-71 interferes with direct cell-to-cell transmission of HCV. Finally we evaluated the in vivo efficacy of mAb16-71 in ‘human liver uPA-SCID mice’ (chimeric mice). A two-week anti-SR-BI therapy that was initiated one day before viral inoculation completely protected all chimeric mice from infection with serum-derived HCV of different genotypes. Moreover, a 9-day post-exposure therapy that was initiated 3 days after viral inoculation (when viremia was already observed in the animals) suppressed the rapid viral spread observed in untreated control animals. After cessation of anti-SR-BI-specific antibody therapy, a rise of the viral load was observed. Conclusion Using in vitro cell culture and human liver-chimeric mouse models, we show that a human monoclonal antibody targeting the HCV co-receptor SR-BI completely prevents infection and intrahepatic spread of multiple HCV genotypes. This strategy may be an efficacious way to prevent infection of allografts following liver transplantation in chronic HCV patients, and may even hold promise for the prevention of virus rebound during or following anti-viral therapy.

HDL in Infectious Diseases and Sepsis

“…So far small molecules and mAbs targeting SR-BI and interfering with HCV infection have been described (Bartosch et al 2003;Catanese et al 2007;Syder et al 2011). A codon-optimized version of this mAb has been demonstrated to prevent HCV spread in vivo (Meuleman et al 2012), and ITX5061, a SR-BI inhibitor, is in clinical development as HCV entry inhibitor (phase I, http:// clinicaltrials.gov/ct2/show/NCT01560468?term¼ITX+5061&rank¼3).…”

Entry and replication of recombinant hepatitis C viruses in cell culture

“…[85] (see Table 1) is particularly amenable to investigate cell-to-cell transmission [85,102,188] as it allows at the same time distinguishing two different cell populations (producer and target cells) and tracking rare infection events at the single cell level. As an alternative to using two cell populations, counting the number of cells per infection focus after culture under an agarose overlay has been used as an estimate of cell-to-cell transmission efficiency [171,189].…”

Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb

“…We also investigated whether the CLDN-1 antibodies B9X and D10X could synergize with the anti-SRB1 antibody C-1671, which potently inhibits infection and spread in vivo in the human liver-chimeric mouse model (Meuleman et al, 2012). Combination of C-1671 with D10X resulted in measurable synergy when tested against four virus strains, including two clinically derived isolates.…”

“…mAbs against CD81 and SRB1 have been shown to inhibit HCV infection in vitro and in vivo. In particular, we previously showed that the human anti-SRB1 mAb C-1671 completely prevents infection and intrahepatic spread of multiple HCV genotypes in vivo in human liver-chimeric mice (Meuleman et al, 2012). Human mAbs against CLDN-1 and OCLN have not been reported yet, but rat, mouse and mouse/human chimeric anti-CLDN-1 antibodies were found to efficiently inhibit infection by HCV of major genotypes in cell culture (Fofana et al, 2010;Yamashita et al, 2015) and some of them eliminate chronic HCV infection without detectable toxicity when administered to human liver-chimeric mice Mailly et al, 2015).…”