Session Title: LATE BREAKERS
Presentation Date: Apr 23 - Apr 25, 2009
A NOVEL HUMAN MONOCLONAL ANTIBODY DIRECTED AGAINST THE E2 GLYCOPROTEIN OF HEPATITIS C VIRUS (HCV) PREVENTS INFECTION IN CHIMPANZEES
B.M. Blair1, T.J. Broering1, G.J. Babcock1, G. Szabo2, R.W. Finberg2, P.S. Cheslock1, M. Knauber1, B.A. Leav1, R. Lanford3, R.H. Purcell4, D.M. Ambrosino1, D.C. Molrine1
1MassBiologics, University of Massachusetts Medical School, Boston, 2University of Massachusetts Medical School, Worcester, MA, 3Southwest Foundation for Biomedical Research, San Antonio, TX, 4National Institute of Health, Bethesda, MD, USA
Background: HCV infection is a leading cause of liver transplantation and there is an urgent need to develop therapy to reduce rates of re-infection of transplanted livers.
Methods: Using transgenic mice (HuMAb, Medarex), we have developed a fully human monoclonal antibody to a linear epitope of HCV E2 glycoprotein MBL-HCV1 that neutralizes pseudoviruses from multiple HCV genotypes. We then tested the ability of MBL-HCV1 to neutralize infectious, replication competent HCV in a cell culture assay using HCVcc 2a strain JFH1/J6. Concentrated cell culture supernatants of JFH1/J6 virions were pre-incubated with MBL-HCV1, applied to Huh 7.5 cells and HCV RNA infection measured by qRT-PCR. MBL-HCV1 completely neutralized HCVcc at concentrations as low as 0.15µg/ml. Based on these in vitro results, the ability of MBL-HCV1 to prevent HCV infection in uninfected chimpanzees was assessed. Three chimpanzees received a single dose of 0mg/kg, 50mg/kg or 250mg/kg of MBL-HCV1 intravenously before challenge with 32 CID of HCV 1a strain H77. Animals were followed for 20 weeks with weekly PCR based viral loads [Lower Limit of Quantification (LLQ) = 500 Genomes/mL (Ge/mL)] as well as clinical and safety laboratory assessments.
Results: Infusion of MBL-HCV1 was safe and well tolerated. No HCV RNA was detected in the serum of the 250mg/kg dosed chimp through week 20. A subset of samples through day 56 was also measured in a transcription-mediated amplification assay (LLQ = 50 Ge/mL) and none of these tested positive. In contrast, the 0mg/kg and 50mg/kg dosed chimps both became infected by Day 14. To investigate the impact of MBL-HCV1 on viral clearance, the 0mg/kg dosed chimp was administered 250mg/kg of MBL-HCV1 at day 42 when viral load measured 1.0 x 105 Ge/mL. At day 49, the viral load was undetectable before rebounding at day 56 to 2.8 x 104 Ge/mL.
Conclusions: These findings suggest that a human monoclonal antibody directed to a conserved epitope of HCV E2 glycoprotein neutralizes infectious, replication competent HCV and prevents infection in the chimpanzee model of HCV disease. A phase I study is planned.