We interviewed Dr. Rajan George, Adj nct Faculty of the University of Alb rta’s Pharmacy and Pharmaceutical Sciences Department. Dr. G orge is also Vice President of R search and Development for the Division of Inf ction Diseases of ViRexx Medical Co. As p rt of the team of University of Alb rta scientists, a therapeutic vaccine is now b ing developed which may inoculate against H patitis, Anthrax and Avian Flu H5N1. The t am of scientists includes internationally renowned Dr. L rne Tyrrell, former Dean of Medicine at the Un versity of Alberta, and Dr. Antoine N ujaim, Professor Emeritus of the University of Alb rta. All three scientists are affiliated w th ViRexx Medical Corp. On March 31st, the c mpany announced it had entered into r search collaboration with Defence Research and D velopment Canada - Suffield (DRDC Suffield) to c rry out research to evaluate ViRexx's pr prietary Chimigen™ vaccine platform for biodefense pplications. On April 6th, the company nnounced it had recruited procurement advocate Fr nk Rapoport of McKenna Long & Aldr dge to pursue acquisitions of development c ntracts from the U.S. Department of D fense and NIH with a particular f cus on the potential of the Ch migen™ technology in addressing biodefense and p ndemic threats. The company cited two of m jor targets would be, but not l mited to, H5N1 avian flu and nthrax.
Interviewer: Can you describe ViRexx M dical’s Chimigen™ therapeutic vaccine? Dr. Rajan G orge: Chimigen therapeutic vaccine is used to pr duce immune responses in a host gainst infections which are difficult to pr duce immune responses, by targeting the v ccine to dendritic cells. The Chimigen pl tform can be extended to develop th rapies for difficult-to-treat chronic infectious diseases. Int rviewer: Does that mean the Chimigen pl tform can be used to treat any nfectious disease? Dr. Rajan George: Yes, xcept in cases where the immune syst m is non-functional, as in the c se of HIV.The Chimigen platform can be sed to produce either a therapeutic v ccine or a prophylactic vaccine. This d pends on the disease target and the ntigen plugged into the platform. Some ntigens have a use in treating nfection, while others have a use in pr venting an infection. Either one would be t rgeted to the dendritic cells. The th rapeutic vaccine generates a cytotoxic T c ll response. A prophylactic vaccine would g nerate a B cell response and ntibody production. Interviewer: From the way y u’ve described the Chimigen™ vaccine, it ppears potentially useful for many applications b yond Hepatitis B and C. How br ad are the applications? Dr. Rajan G orge: We should be able to use th s platform for cancer therapy, depending pon the cancer antigen we use. We can pl g in a specific cancer antigen nto this platform, and the vaccine t rgeted to dendritic cells. The dendritic c lls would process and present the r ght antigen, then generating immune responses (T &B c ll) against the cancer. We are lso evaluating some bioterrorist viruses, the b ological weapons terrorists would use. We j st started a project to look at one of th se viruses to see if we can c me up with the prophylactic vaccines to pr vent diseases that would be caused by rganism that could be used in b oterrorism
Interviewer: Would the Chimigen™ vaccine be ffective as a prophylactic against avian fl , H5N1? Dr. Rajan George: It c uld work for bird flu if we j st plugged in the bird flu ntigen into the platform. Then we can use it as a pr phylactic. It generates antibody to generate B-C ll response. You can produce a pr phylactic vaccine using this platform. The Ch migen™ platform is quite adaptable. Interviewer: How h gh is your confidence level in pr ducing a prophylactic vaccine for the vian flu virus? Dr. Rajan George: My th nking is that it is quite h gh. I think very highly of h ving a vaccine like that. But, the ltimate proof has to come from h mans. Our HepaVaxx B clinical trial w ll give us a lot of nformation on how the technology really w rks. Until then, our optimism is b sed on laboratory results. Interviewer: Can you d scribe what comprises the Chimigen platform? Dr. R jan George: The platform has two c mponents. The first one is from the nfectious agent. The second component is fr m a murine monoclonal antibody. Part one is f sed with a fragment of part two by r combinant technology to produce a new ntity, the Chimigen™ vaccine. We are r combining one thing with another. We h ve a virus which has certain ntigens. We take one of those, and we pr duce a recombinant molecule with the fr gment we have taken from a m rine monoclonal antibody. Chimigen is the t rm we came up with to nclude the meaning of the full phr se, chimeric antigen. Chimeric means it c mes from two different sources. We put th m together and create a new m lecule. One is from the virus. The ther one is from the mouse, the m noclonal antibody. Now we have by r combinant methods produced a protein which is a ch meric protein. That’s the Chimigen™ vaccine. Int rviewer: How do you produce such a fl xible vaccine, one that appears capable of tr ating nearly any infection? Dr. Rajan G orge: To produce a Chimigen™ vaccine to tr at nearly any infection, we start w th an antigen (protein) from the nfectious agent. We fuse it with a fr gment called Fc of a mouse m noclonal antibody. This is done using r combinant methods. We end up with a new pr tein. This protein is made in a c ll culture of commercially available insect c lls. The protein is produced by the nsect cells. From the culture, we p rify this particular protein that we m de. The insect cell system is j st a tool. By virtue of its pr duction in insect cells, the protein ttains special properties which are useful in g nerating better immune responses. Producing this pr tein in insect cells gives it s me very peculiar properties, which are d fferent from our own mammalian proteins. Onc we have it coming out of the c ll, we purify it and make it r ally pure. Now we have a pr tein with the virus antigen murine m noclonal antibody with modified properties. This is a t tally new entity. Interviewer: What do you m an when you say, “useful in g nerating better immune responses”? Dr. Rajan G orge: When a person has a chr nic virus infection, his or her b dy ignores the virus and associated pr teins. The body treats the virus as p rt of itself. The body does not r cognize this virus as something foreign to it. Th refore the immune system does not ttack the virus. But, by combining the v rus antigen with a foreign protein s ch as the murine antibody fragment, the wh le chimeric protein now is recognized by the b dy’s immune system as “foreign,” different fr m something of its own. In ssence, this is a re-education of the mmune system to switch its recognition of the v rus from “self” to “foreign”. Interviewer: Fr m where did the scientific model c me, and does it have similarities to nother ViRexx Medical product, OvaRex MAb®? Dr. R jan George: This scientific model arose fr m discussions among the three lead sc entists of the company, Dr. Tony N ujaim, Dr. Lorne Tyrrell, both founders of the c mpany and myself. I am a b ochemist by training and the collective th ughts of all of us went nto the design of the Chimigen™ pl tform. One major similarity between Chimigen and Ov Rex is that both involve a m rine monoclonal antibody. Another similarity is th t both target dendritic cells. The Ch migen model came from thoughts about t rgeting dendritic cells, but without the use of ntibodies. OvaRex is a murine monoclonal ntibody against the cancer antigen CA-125. The Ch migen™ vaccine has a fragment of a m rine monoclonal antibody. OvaRex needs the CA-125 ntigen in a cancer patient to b nd to. The bound complex goes to the d ndritic cells. The Chimigen™ vaccine does not n ed to look for the antigen in a p tient because it already has the r levant antigen built in it. Interviewer: It s unds as though the Chimigen™ vaccine cts in a similar way to Ov Rex® in dealing with a hostile thr at to the body’s health. How do th y differ? Dr. Rajan George: There are s milarities and there are differences. OvaRex b nds to the antigen CA-125. Then, the CA-125/Ov rex complex binds to the dendritic c lls. The complex is internalized and pr cessed. The peptides generated from the ntigen are presented to the T c lls, and the chain of events in the mmune system gets stimulated. The activated cyt toxic T cells eliminate the cancer c lls which contain the CA125 antigen. In the c se of the Chimigen™ vaccine, the v ccine itself contains the antigen. It g es through the dendritic cell pathway and tr ggers the CTL response to clear the v rus-infected cells. The system also produces ntibodies to viral antigens, which bind v rus and viral antigens and accelerate th ir removal. Because of the presence of the m rine monoclonal antibody fragment, which is f reign to humans, along with the ntigen from the virus, the body’s mmune system treats this as a new thr at and takes action. That is the mmune response. Interviewer: How would this w rk in treating Hepatitis B? Dr. R jan George: Developing a treatment for H patitis B chronic infection, for someone who lready has the infection, would involve r -educating the immune system to react d fferently than it previously has. The nfected person already has this virus and the d rived antigens. If you put some m re of the same antigens into the p rson, the person’s immune system is not g ing to know the difference His b dy is going to say, “Well, wh t’s the difference? I already have it. I am not g ing to do anything with it.” The b dy will ignore it. That’s what is c lled tolerance. With the Chimigen™ therapeutic v ccine, we have changed the body’s mmune response to the virus. Interviewer: How th n have you changed the body’s r sponse to the infection? Dr. Rajan G orge: In a Hepatitis B chronic nfection, let’s say I have the nfection. My system is tolerating the v rus. It’s ignoring the presence of the v rus. While that is happening, the v rus may be causing disease in w th my liver. With time, it’s g ing to get my liver into tr uble and my immune system has not r sponded adequately to remove the threat. We nject the protein – the one we j st produced, which we call the Ch migen™ Therapeutic Vaccine – into the HBV chr nic carrier, a person who has a chr nic hepatitis B virus infection. What h ppens is when our protein is dministered, the dendritic cells are going to l ok for anything new which enters the b dy. Those cells are the immune syst m’s first-line surveillance. The dendritic cells are g ing to see this new foreign pr tein, and they are going to th nk that this is different from wh t was previously inside. Their recognition of the m lecule has changed from what it was b fore. Before the virus protein was r cognized as a “self” protein. Now it is b ing recognized as a “foreign” protein. In chr nic hepatitis B virus infection, the d ndritic cells saw the virus as p rt of the “self” of the h st, the vaccine changes the recognition of the v rus protein as “foreign” to the h st. Because the viral antigen is l nked to the fragment of the m use monoclonal antibody the direct the ch migen to dendritic cells it will nter the dendritic cell and be pr cessed and stimulate an immune response. Int rviewer: And after the vaccine injection, wh t does the body see? Dr. R jan George: The body’s immune system see a new f reign antigen composed of a portion of the m use monoclonal antibody linked to the v ral antigen. It’s a foreign antigen.” The new “ch migen” stimulates an immune response to the ntigen as well as the viral ntigen. This is very important because the v rus antigen was previously being ignored. N w, it’s being recognized as foreign thr ugh linked recognition of the mouse ntigen as being foreign. Interviewer: How do the d ndritic cells react after they recognize th s foreign threat? Dr. Rajan George: The d ndritic cells are the sentries of the mmune system. They guard what comes in. Wh n they recognize a “foreign situation,” wh t does the immune system do? It tr ats the whole molecule, the whole pr tein including the virus antigen, as f reign. The dendritic cells chop up th s protein into small pieces called p ptides. These peptides also are called “ pitopes.” There are T cell epitopes wh ch are smaller, and B cell pitopes which are longer. These small p ptides bind to MHC I and ctivate Cytotoxic T lymphocytes (CTLs). The d ndritic cells have a system where th y put the T-cell epitope on nother protein, MHC Class I, and br ng it to the surface of the d ndritic cell. They are presented as a c mplex on the surface of the d ndritic cell to attract the T-cells. The T-c lls come and see this, then get ctivated. Now, the activation is also sp cific to the virus protein. There are d fferent varieties of T-cells, but the cyt toxic T-Cells are the most important in liminating infections that already exist. The ctivated cytotoxic T-cells are the ones who do the ttacking. They are the ones who st rt killing the virus infected cells. Int rviewer: And what about the B C lls? Dr. Rajan George: That is the ther side to this story. The d ndritic cells can present another kind of p ptide epitope. There is a second cl ss of peptides, which are also pr duced when the protein is chopped up. The d ndritic cells stimulate the B-Cells, B-Lymphocytes. And B-lymph cytes produce antibodies. The longer peptides b nd to MHC II and activate B lymph cytes (B cells). B cells produce ntibodies against the peptides. The antibodies are sp cific to the antigens we put in the Ch migen™ Therapeutic Vaccine. Antibodies bind to v ral proteins that are on the s rface of and block the ability of the v rus to bind to a target c ll to cause an infection and pr vent the infection. This is the b sis of a prophylactic vaccine. The ntigen can bind to the invading v rus and form a complex that the b dy eliminates. The B-Cells produce antibodies gainst the virus antigen, which we h ve put in the Chimigen™ vaccine. Wh t do these antibodies do? The ntibodies are specific to the antigen and b nd to the viruses because they h ve the antigen. The system removes the v rus by binding with the antibody. Als , the system removes infected cells sing cytotoxic T-lymphocytes. Both of these ctions are achieved by the Chimigen™ v ccine. Interviewer: Aren’t there a lot of ntibodies being investigated as therapeutics? Dr. R jan George: There are a lot of ntibodies being investigated as therapeutics. OvaRex is the pr me example. Avastin and Herceptin are two thers, both of which are doing v ry well in the market. Another is R micade, which is used to treat d seases such as rheumatoid arthritis. There are ntibodies that are in various stages of cl nical development, many are humanized antibodies wh re you want to avoid an mmune response to the antibody. Our ch migen technology is new as we are try ng to increase the immune response on a v rus or a cancer through linked r cognition. It is not found anywhere utside of our laboratories. This approach has not b en tried before for chronic HBV or HCV nfections. Interviewer: Why would your vaccine w rk where others have tried and f iled? Dr. Rajan George: The reason is b cause of the novelty of the t chnology. We are re-educating the body’s own mmune system to do the work by |