| A SCIENTIST'S 20-YEAR UNFINISHED JOURNEY TO | | | | soon as you stop the therapy, the virus comes |
| TREAT HBV MAY OPEN THE DOOR TO A NEW CLASS OF | | | | right back up." He told us the sustained |
| FLEXIBLE VACCINESWhile preparing a lecture in | | | | viral response is only about two to three |
| biochemistry and virology for his graduate | | | | percent. Only about 30 percent remain free of |
| students at the University of Alberta in the | | | | the virus, about one year after patients have |
| early 1980s, Dr. Lorne Tyrrell ran across a | | | | stopped taking lamivudine."How do you break |
| study just published in the medical journal, | | | | tolerance?" Tyrrell asked himself, hoping to |
| Cell. The research by William Mason and Jesse | | | | develop a way to stimulate an immune |
| Summers, entitled "Replication of Hepatitis | | | | response. All of the patients, he had |
| B," discussed their study of the hepatitis B | | | | observed, seemed to be tolerant of the |
| virus in infected duck liver.After studying | | | | hepatitis B virus. He pondered the dilemma, |
| their duck model theory, Tyrrell speculated | | | | "Was there some way to break tolerance to |
| if the hepatitis B virus (HBV) might be | | | | hepatitis B by stimulating the immune |
| susceptible to antiviral agents, and | | | | response?" Tyrrell studied what others were |
| consulted with a colleague, who specialized | | | | attempting and wasn't satisfied with the |
| in nucleoside chemistry. Both medical | | | | approaches others were taking to stimulate |
| professors became excited about the | | | | immune response. His ViRexx Medical research |
| possibility of inhibiting the HBV virus with | | | | team brainstormed about different ways to |
| nucleoside analogues. Thus began the | | | | target the antigen into the dendritic |
| infectious disease specialist's first leg of | | | | cells."That's where we came in with the |
| a journey, which led to the use of lamivudine | | | | Chimigen (TM) technology," Tyrrell said. |
| as a therapy for chronic HBV infections.More | | | | "The dendritic cells have receptors on their |
| than 350 million people across the world, | | | | surface that will bind the Fc portion of an |
| especially in Asia, now had new hope, some | | | | antibody." He pointed out a key feature of |
| for their lifelong infections contracted | | | | the Chimigen (TM) platform, "We used the Fc |
| vertically at birth from their mothers. In | | | | portion of a murine (mouse) antibody to hook |
| 2003, the Center for Disease Control | | | | onto our hepatitis B antigens. This would |
| estimated 73,000 Americans were infected with | | | | direct the viral antigens into dendritic |
| HBV, and about 5,000 die each year from | | | | cells in vivo." Because the dendritic cells |
| sickness caused by HBV. It is reportedly 100 | | | | are the sentries of the immune system, they |
| times more contagious than the AIDS virus. | | | | guard what comes in. Recognizing a 'foreign |
| Many in North America, who had been infected | | | | situation' in the murine antibody, it treats |
| with the virus from sexual transmission or | | | | the whole molecule including the virus |
| intravenous drug use, were offered a | | | | antigen as foreign.LINK RECOGNITION MAY HOLD |
| potentially life-saving therapy.Licensed in | | | | THE KEYDr. Rajan George, ViRexx Medical's |
| 1998, lamivudine is now used in 120 countries | | | | vice president of research and development, |
| as a standard therapy for chronic HBV | | | | told us, "The dendritic cells chop up this |
| carriers. The compound is also used in | | | | protein into small pieces called peptides, |
| combination with other drugs, such as | | | | also known as epitopes. The dendritic cells |
| protease inhibitors, for HIV therapy. | | | | have a system where they put the T-cell |
| Development rights were licensed to Glaxo | | | | epitope on another protein, MHC Class I, and |
| Wellcome in 1990, which is now sold under the | | | | bring it to the surface of the dendritic |
| brand name Epivir(R). For his pioneering | | | | cell. They are presented as a complex on the |
| efforts in developing the antiviral agent, | | | | surface of the dendritic cell to attract the |
| Dr. Tyrrell was awarded the gold medal by the | | | | T-cells." When the T-cells arrive to inspect |
| Canadian Liver Foundation and the Canadian | | | | the foreign entity, the cytotoxic T-cells are |
| Association for the Study of Liver in 2000. | | | | activated. Then, they begin attacking and |
| In 2005, he won the prestigious EnCana | | | | killing the virus-infected cells.Research at |
| Principal Award for his development of the | | | | Tokyo's Cancer Institute Hospital, published |
| first effective oral medication for Hepatitis | | | | in 1987 in Nippon Sanka Fujinka Gakkai |
| B.HIS UNANSWERED QUESTIONS LAUNCHED A NEW HBV | | | | Zasshi, suggested a feasibility of linked |
| INVESTIGATIONDespite the awards and | | | | recognition of a virus antigen as a helper in |
| recognition, questions remained for Dr. | | | | tumor immunity with a target antigen. In the |
| Tyrrell about the shortcomings of lamivudine. | | | | case of ViRexx Medical, Tyrrell's team has |
| He was troubled that some viruses would | | | | created a new molecule, called "chimigen." |
| develop resistance to the compound. "I was | | | | The term is shorthand for a chimeric antigen, |
| disappointed the sustained viral response was | | | | meaning it is an antigen created from two |
| not complete," Tyrrell told us. In April | | | | different sources, part virus and part murine |
| 2003, the Journal of Antimicrobial | | | | monoclonal antibody.Dr. Tyrrell's work at |
| Chemotherapy published a study in Japan | | | | ViRexx Medical with Dr. George suggested the |
| showing, "long-term (lamivudine) therapy is | | | | linked-recognition theory might be the key to |
| associated with increased emergence of | | | | breaking tolerance. Dr. George emphasized, |
| lamivudine-resistant strains of HBV." | | | | "The new 'chimigen' stimulates an immune |
| Researchers concluded in this study, "The | | | | response to the antigen as well as the viral |
| therapeutic challenge to effectively treat | | | | antigen. This is very important because the |
| chronic HBV infection continues."Having | | | | virus antigen was previously being ignored." |
| screened lamivudine for use in Hepatitis B at | | | | That brings us back to why lamivudine had |
| Glaxo's research lab at the University of | | | | limited success. The immune systems of some |
| Alberta, Dr. Tyrrell was able to observe the | | | | HBV carriers failed to recognize the viral |
| immune response of various HBV patients. | | | | infection as a threat to the body. Tyrell's |
| "What really got me interested in doing more | | | | ViRexx Medical research team hopes the body's |
| work in this area was that we noticed | | | | immune system sees the threat, thus |
| patients, who have an immune response to the | | | | stimulating the immune system, and breaking |
| virus and take lamivudine, will have a better | | | | tolerance. It appears Dr. Tyrell may soon |
| sustained response rate," Tyrrell explained. | | | | find out whether or not the questions he |
| "A patient with elevated liver transaminases | | | | asked will bring the answers he hoped for.END |
| taking lamivudine had a higher probability of | | | | OF PART ONEJames Finch contributes to and |
| a sustained viral response," Tyrrell said | | | | other publications. Visit to read all of his |
| with excitement in his voice. "In a patient | | | | articles. Write to James Finch at Visit to |
| with normal liver enzymes, who gets | | | | find out more about the Chimigen(TM) |
| lamivudine, the virus will go down, but as | | | | platform. |