HuMax-HepC™ is a human antibody in pre-clinical development for the treatment
of
Hepatitis C virus re-infection after
liver transplantation. Genmab acquired the rights to HuMax-HepC from the
administrators of Connex GmbH and from INSERM.
Hepatitis C Virus
Worldwide more than 170 million people are chronically infected with the
Hepatitis C virus (HCV), including 3.9 million in the United States and 8.9
million in Europe. Most infected people develop increasing liver fibrosis
over time that can lead to cirrhosis, liver failure or liver cancer.
From population-based studies it is estimated that in the United States
8,000–10,000 deaths occur each year due to HCV-related chronic liver
disease. Moreover, Hepatitis C is the main cause of about half of the
estimated 10,000 liver transplants in Europe and the United States each
year. A major complication of liver transplantation in HCV-patients is
re-infection of the graft by HCV. Studies conducted in several laboratories
support the rationale for using antibodies to prevent liver infection or
re-infection with HCV.
HCV is an enveloped single-stranded RNA virus, of which there are six major
genotypes distributed around the world. The most prevalent genotypes are
1a, 1b, 2 and 3. CD81 is a receptor for viral entry into human cells;
however, other molecules have also been implicated in HCV cellular
infection.
Pre-clinical Studies
Our HuMax-HepC antibody was originally isolated from a patient who
suffered from mild chronic hepatitis due to an infection with HCV. In
pre-clinical studies, we have shown that HuMax-HepC is broadly
cross-reactive with several HCV genotypes, including 1a, 1b, 2a, 3a, and
4a. HuMax-HepC binds to a conformational epitope of envelope protein 2 (E2)
and in pre-clinical trials, the antibody potently neutralized binding of
HCV-E2 to susceptible cells.
In a novel animal model, mice with a compromised immune system were
transplanted with human liver cells (hepatocytes) and exposed to a mixture
of patient-derived HCV of different genotypes. Replication of HCV was
not observed in 5 of 6 mice (83%) treated with HuMax-HepC, indicating that
HuMax-HepC completely prevented HCV infection. The sixth mouse was
infected with HCV, but the virus was subsequently cleared. In
comparison, 5 of 6 mice who received a control antibody developed and
sustained a robust HCV infection.
Selected Scientific References:
Bartosch B, Dubuisson J, and Cosset FL. Infectious hepatitis C virus
pseudo-particles containing functional E1-E2 envelope protein complexes.
J Exp Med. 2003; 197(5): 633-42.
Hsu M, et al. Hepatitis C virus glycoproteins mediate pH-dependent cell entry
of pseudotyped retroviral particles.
Proc Natl Acad Sci
USA. 2003; 100(12): 7271-6.
Gardner JP, et al. L-SIGN (CD 209L) is a liver-specific capture receptor for
hepatitis C virus.
Proc Natl Acad Sci USA. 2003; 100(8):
4498-503.
Pohlmann S, et al. Hepatitis C virus glycoproteins interact with DC-SIGN and
DC-SIGNR.
J Virol. 2003; 77(7): 4070-80.