Human Monoclonal Antibody MBL-HCV1 Delays HCV Viral Rebound Following Liver Transplantation: A Randomized Controlled Study

Abstract

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/ml) from baseline was significantly greater (P=0.02) for the antibody-treated group (range −3.07 to −3.34) compared to placebo group (range −0.331 to −1.01) on days 3 through 6 post-transplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, P <0.001). As with other HCV monotherapies, antibody-treated subjects had resistance-associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway. ClinicalTrials.gov Identifier: NCT01121185 funded by MassBiologics

Structural Basis for Penetration of the Glycan Shield of Hepatitis C Virus E2 Glycoprotein by a Broadly Neutralizing Human Antibody

“…Crystal structures of the wild-type E2 412-423 epitope bound to HCV1 and AP33 showed that, whereas the side chain of Asn-417 points away from the antibody, Asn-415 is buried within the peptide-antibody interface (35)(36)(37)(38). Consequently, attachment of a glycan at Asn-415, but not at Asn-417, would create major steric clashes with HCV1 and AP33, resulting in abrogation of antibody binding and HCV escape, as observed in resistance selection studies (29,35,39). Notably, liver transplantation patients with HCV who were treated with HCV1 showed rebounds in viral load at various times following transplantation (39).…”

“…Consequently, attachment of a glycan at Asn-415, but not at Asn-417, would create major steric clashes with HCV1 and AP33, resulting in abrogation of antibody binding and HCV escape, as observed in resistance selection studies (29,35,39). Notably, liver transplantation patients with HCV who were treated with HCV1 showed rebounds in viral load at various times following transplantation (39). These rebounds were consistently associated with mutations in the E2 412-423 epitope known to confer resistance to HCV1, in particular N417S.…”

“…Accommodation of the Glycosylation Shift to Asn-415 of E2 412-423 -Escape of HCV from neutralization by the E2 412-423 -specific mAbs HCV1, AP33, and 3/11 is the result of adaptive mutations at Asn-417 (N417S and N417T) that cause a glycosylation shift from Asn-417 to Asn-415 in the E2 protein (29,35,39). In marked contrast to these mAbs, HC33.1 can penetrate the glycan shield at Asn-415 originating from the glycosylation shift (14,28).…”

A single amino acid change in the hypervariable region 1 of hepatitis C virus genotype 4a aids humoral immune escape

“…Cytotoxic T-lymphocytes drive evolution of the HVR1, which can lead to the emergence of escape variants (Cox et al, 2005; Ray et al, 2005). However, there is an absence of direct in vivo evidence of humoral immune escape by host-derived antibodies and viral glycoproteins (Chung et al, 2013).Previous research from our group has observed, over a near 10 year period, the emergence, dominance and disappearance of distinct but related lineages (L1 and L2) in a treatment-naive patient chronically infected with HCV genotype 4a (Palmer et al, 2014). L1 dominated the virome for the first 8 years of the sampling period prior to population collapse and this led to the concomitant rise to prominence of L2.…”

“…Cytotoxic T-lymphocytes drive evolution of the HVR1, which can lead to the emergence of escape variants (Cox et al, 2005; Ray et al, 2005). However, there is an absence of direct in vivo evidence of humoral immune escape by host-derived antibodies and viral glycoproteins (Chung et al, 2013).…”