The HBV surface antigen (HBsAg) was first described as the Australian antigen by Dr. Baruch Blumberg in 1967 (a discovery which won him the Nobel Prize for Medicine in 1976). The HBV virus has evolved to saturate the blood with the surface antigen protein (HBsAg) by the production and release of small viral like particles called subviral particles. These particles are not infectious but make up the bulk of viral protein in the blood and are packed with the HBsAg protein. Mounting evidence is now showing that the HBsAg protein acts directly to suppress both innate and adaptive immune responses to HBV infection (see Figure 1 and references below) and allow HBV infection to be chronically maintained in the liver. This inhibition of the immune system by HBsAg is likely one of the main reasons why HBV infection persists for so long. In fact, HBV infection can be described as a chronic immunological disorder as well as a viral infection. Figure 1 illustrates the relative production and immunological impact of viruses and subviral particles during HBV infection.
Figure 1. The relative production of HBV subviral particles and virions during HBV infection and their impact on inhibition of the immune response to HBV infection.
The main cause for the lack of a curative response with existing therapies (e.g. interferons or HBV polymerase inhibitors) is that none of these treatments targets the elimination of the HBV surface antigen from the blood. While these treatments may eliminate the HBV virus from the blood, they do little to block the release of HBsAg into the blood. As a result, many of these therapies only have a marginal effect on restoring the patients’ HBV immune response (see figure 2).
Figure 2. The limited impact of current HBV antiviral therapies on HBV mediated immune suppression.
NUCLEIC ACID-BASED POLYMERS (NAPs) – Novel therapeutic agents for the treatment of chronic hepatitis, NAPs were discovered at Replicor in 2002 and utilize the unique, sequence independent properties of phosphorothioated oligonucleotides to generate novel amphipathic polymers which have a very broad spectrum antiviral activity against enveloped viruses.
Replicor’s first NAP drugs to be used in the clinic, REP 2055 and REP 2139, are first-in-class HBsAg release inhibitors. By interfering with the biochemical processes involved in the formation of subviral particles within infected hepatocytes, NAPs prevent the release of these particles (and the HBsAg they carry) from infected liver cells (hepatocytes). The administration of Replicor’s drug to animals or humans results in a rapid reduction and elimination of hepatitis surface antigen in the blood without affecting the production of HBV virions. This HBsAg reduction is associated with the restoration of the immune system’s capability to fight the infection. In other words, the removal of surface antigen from the blood gives patients the ability to successfully fight their infection on their own. In addition, because of its mechanism of action, the development of resistance to Replicor’s drug is very unlikely. The mechanism of action of NAPs can be seen in figure 3.
Figure 3. The mechanism of action of NAPs and their effect on HBV-mediated immune suppression.
Interim clinical data from Replicor’s second phase I/II trial shows that REP 2139 is well tolerated and has substantial antiviral activity in patients suffering from chronic HBV infection. The administration of REP 2139 results in the rapid elimination of surface antigen in the blood of human patients which leads to the restoration of immune function as demonstrated by the return of HBsAg antibody production in most patients and a substantial reduction of viral DNA titers in the blood.
The following graph (Figure 4) demonstrates the control of HBV viremia in the blood of patients under NAP therapy (as measured in copies per ml (cpm) of HBV DNA in the serum) obtained in 8 out of 9 patients treated sequentially with REP 2139 alone followed by REP 2139 and immunotherapy given in combination for a duration of 12 to 26 weeks.
Figure 4: Antiviral response (serum viremia, measured by HBV DNA) in patients receiving REP 2139-Ca based combination therapy. Solid lines indicate on treatment antiviral response. Dotted lines indicate establishment of complete control of infection in 8 / 9 (88%) of patients after withdrawal of all treatment. Patients received immunotherapy (Pegasys® or Zadaxin®) for the last 12 – 26 weeks of treatment. LLOQ indicates the lower limit of quantification of HBV DNA possible with the Roche cobas® test.
Additional information and clinical data can reviewed in the Conference Presentations section.
For more information on the immune-inhibitory properties of HBsAg please refer to the following:
Cheng et al., 2005. Journal of Hepatology, 43:4 65-471
Op den Brouw et al., 2009. Immunology, 126: 280-289
Shi et al. 2012 PLoS ONE 7: e44900
Vanlandschoot et al., 2002. J. Gen. Virol., 83: 1281-1289
Woltman et al. 2011 PLoS ONE 6: e15324
Wu et al., 2009. Hepatology, 49: 1132-1140
Xu et al., 2009. Molecular immunology, 46: 2640-2646