Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees

Abstract

Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412–423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5–1.0 log10 reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation.

Structural evidence for a bifurcated mode of action in the antibody-mediated neutralization of hepatitis C virus

“…Several segments of the E2 protein have been identified as key components of conformational or linear epitopes that are critical to antibody-mediated neutralization of HCV in vitro (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Interestingly, naturally evoked antibodies and those produced in vitro that are specifically directed against a short peptide located in the E2 protein between residues 427-446, also known as epitope II, displayed one of three activities: virus neutralization, E2 binding but no neutralization, or interference with virus neutralization (15,16).…”

Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance

“…Infusion of bNAbs is protective against infection in animal models of HCV (17,18), and a recent study also showed that bNAbs could abrogate established HCV infection in a humanized transgenic mouse model (19). Given the efficacy of these bNAbs in blocking HCV infection, the molecular and genetic features of bNAbs and their epitopes may serve as a useful guide for rational HCV vaccine design.…”

Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles

“…HCVpp have greatly advanced the understanding of HCV entry and neutralization by antibodies (Giang et al, 2012;Law et al, 2008;Morin et al, 2012;Osburn et al, 2014;Pestka et al, 2007). This model system has been used extensively in identifying HCV cell surface receptors required for viral entry (Bartosch et al, 2003;Cormier et al, 2004;McKeating et al, 2004;Zhang et al, 2004), and studies using HCVpp have established that neutralizing antibodies can drive evolution in vivo of HCV E1E2, leading to neutralization escape (Dowd et al, 2009;Pestka et al, 2007).…”

“…These HCVcc have been used to further define viral entry pathways (Brimacombe et al, 2011;Carlsen et al, 2013;Mathiesen et al, 2015;Timpe et al, 2008) and to show that broadly neutralizing monoclonal antibodies (bNAbs) can prevent HCV infection in animal models (Forns et al, 2000;Morin et al, 2012;Youn et al, 2005). Panels of HCVcc expressing E1E2 from multiple genotypes have also been used to measure neutralizing breadth of bNAbs (Carlsen et al, 2014;Keck et al, 2008Keck et al, , 2013Law et al, 2008).…”