Auto-Immunity
TBL has successfully developed & tested a technology platform for selective targeting & killing of undesired cells in the human body. The technology was initially developed for selective removal of certain antibody producing B cells for immune modulation/correction. This selective targeting of B cells forms the basis for Transgene’s patented and proprietary platform in developing drugs for conditions such as AIDS, Multiple Sclerosis and such other auto-immune diseases. The AIDS vaccine and the Multiple Sclerosis drug are the first products to come out of it.

Certain humoral (Antibody) responses to the highly changing viral envelopes from retrovirus viruses become undesirable over time as they not only fail to contain the virus but also suppress the cell mediated immunity severely. For example, in HIV infected persons the gp120 specific humoral responses dominate and prevent cell mediated immunity which is clearly evident in case of rapid progressors who have high titers of gp120 specific antibody responses than the slow progressors. We focused on correcting such kinds of immune imbalances by selectively targeting those envelope specific antibody producing B cells. We have developed a design to target gp120 antibody specific B cells and the designed toxin protein could selectively kill the gp120 antibody bearing B cells sparing other types of antibody producing B cells. The molecular biology of the fate of the target cells was extensively studied through cytotoxicity tests (XTT), apoptosis etc.
HIV DRUG

Overview
Current retroviral drugs limit HIV replication but do not eliminate the virus completely as they do not restore the cell mediated attack mechanism on the virus, hence the virus bounces back once treatment is discontinued. Our drug, TBL–1203, is aimed at strengthening cell mediated immunity and complete elimination of the virus, without any need for retro-viral drug therapy. It induces selective cytotoxicity, thereby reversing the process of AIDS in HIV infected people.


Disease Background
Since the first report in 1981, more than 67 million persons have been infected with HIV, and more than 27 million have died of AIDS. More than 40% of new infections worldwide occur among adults in the age range of 15-24 years. In fact, AIDS is now the leading cause of premature death among people 15 to 59 years of age.

HIV is a retrovirus, whose mechanism of action involves directly integrating viral DNA into the host cells’ DNA by means of several critical steps, upon which it is replicated to produce a new progeny of virus particles. HIV adsorption to the cell surface is the first step of infection. This process hinges on the interaction of the negatively charged molecules on the cell surface with the positively charged viral glycoprotein (gp120), produced in precursor form by the envelope gene of HIV, which encodes a 160 kD glycoprotein (gp 160). The gp160 protein is expressed in infected host cells and then cleaved into the extra cellular surface protein gp120 and a transmembrane protein gp41. The transmembrane gp41 protein provides an anchor to which gp 120 is somewhat loosely bound on the surface of infected host cells. Infection of T4 cells and macrophages by HIV is mediated by binding of gp120 to the CD4 receptor protein on the cell surface. HIV is internalized into the cell and replicates by producing new viral genomes and viral proteins, including gp41 and gp120. New virions are produced by budding off from the infected cell membrane. About half of the gp120 protein produced is shed into the circulation, where it can bind to CD4 on non-infected T4 cells.

Infection of T4 cells and macrophages by HIV is mediated by binding of gp120 to the CD4 receptor protein on the cell surface. HIV is internalized into the cell and replicates by producing new viral genomes and viral proteins, including gp41 and gp120. New virions are produced by budding off from the infected cell membrane. About half of the gp120 protein produced is shed into the circulation, where it can bind to CD4 on non-infected T4 cells. Circulating anti gp120 antibodies produced by activated B cell can bind to gp120 on the surface of infected and non-infected T4 cells, resulting in cross-linking and activation of antibody dependent cellular cytotoxicity (ADCC) directed against T4 cells. The depletion of T cells in HIV patients is thought to result in part from B-cell production of antibodies against the envelope protein (e.g., gp120) of the HIV rather than by direct infection with HIV. It is believed that when gp120 is shed from the virus, the protein becomes either free-floating in the bloodstream or is bound to the surface of uninfected cells, particularly T4 cells via the CD4 receptors. Anti gp120 antibodies will naturally cross-link gp120 proteins bound to adjacent CD4 receptors. This cross-linking causes the cell to stop producing IL-2 and the IL- 2receptor, thereby preventing normal cellular function and, initiating apoptosis. Additionally, cross- linking of anti-gp120 antibodies may also block the production of new T4 cells by interfering with multiplying or reproduction of immature T4 cells.


Challenges in developing effective drugs against HIV and AIDS
While the research for an effective HIV vaccine continues, which might take few years to completely realize, there is immediate need for an efficient alternative treatment besides the presentantiretroviral drug therapies for treatment of HIV infected persons. Though the current antiviral drug treatments are effective in controlling the HIV replication to a large extent, are ineffective in mounting the HIV specific, especially envelop specific (gp120) CD4+ Th1 responses, which are proven to be essential for complete viral clearance.
HIV/AIDS remains both a medical and economic challenge in developing countries especially in Sub- Saharan Africa. Unfortunately, after nearly 30 years of research there are still three compelling facts driving the development of new anti-AIDS drugs and delivery systems:
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there is a lack of an effective vaccine or prophylactic agent that would provide protection for the foreseeable future,
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there is a constant need for both less expensive and more tolerable drug therapies, and
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the development of resistant viral strains in treatment-experienced patients continue. The late Dr. Paul Janssen described four ideal characteristics of a novel anti-HIV drug.
   
 

The drug must possess:

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high antiviral activity against both wild-type and mutant virus, thus a drug must be effective despite the genetic flexibility of the virus and it must anticipate resistant strains that may develop once therapy is initiated,
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high oral bioavailability and a long elimination half-life to allow for once daily dosing, which is considered the gold standard of any therapy,
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have minimal adverse effects, which will ultimately impact patient compliance, and

» be easy to synthesize and formulate into dosage forms, which ultimately impact the cost of the drug for both the manufacturer and the patient. However, the development of drugs that meet these criteria is an arduous task.



Scientific Rationale
TBL-1203 is conceptually designed to restore gp120 specific Th1 responses (which have the potential to control HIV) in HIV infected persons through selective abrogation of gp120 antibody producing B cells so that the immune responses will shift towards Th1 type from previously Th2 type.
TBL 1203 is an immune-toxin constructed by recombinant technology that specifically targets and kills the gp120 antibody producing B cells. Removal of these B cells and hence the gp120 specific antibodies through this immune correction mechanism will have many positive effects.


TBL 1203 focuses on the restoration of gp120 specific Th1 responses (which have the potential to control HIV) in HIV infected persons.
The cytotoxin (CTx) targets all APC that have anti-gp120 Ab on their surface which would include all those macrophages (which potentially are the store of the latent HIV virions) actively involved in processing antigen, plus DCs.


Progress
The vaccine has demonstrated exciting results during in-house studies by selective killing of only the HIV infected cells – This sets it apart from any other existing drugs. Pre-clinical animal trials on TBL 1203 are due to commence soon employing special animals such as humanized mice infected with HIV. Decrease in the gp120 antibody titers, increase in the CD4+ count, IFN-γ production etc are to be reconfirmed, among others, in these studies to add strength to already established proof of concept.
MULTIPLE SCLEROSIS DRUG

Disease Background
Multiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the central nervous system (CNS), destroying the myelin and the axon in variable degrees. Multiple sclerosis (MS) is a slowly progressive disease with demyelination resulting in multiple neurological symptoms such as stiffness of gait, weakness of muscles, clumsiness etc. There is no cure for multiple sclerosis. Treatment typically focuses on strategies to treat attacks, to modify the course of the disease and to treat symptoms. The multiple sclerosis (MS) treatments market is one of the largest for CNS disorders, with total pharmaceutical revenues of over $8bn in 2009. Revenues for MS treatments are expected to rise significantly from 2010 to 2025. Rising disease prevalence, expanding patient populations, technological advances and widening healthcare provision for MS all having an impact in driving the market upwards.
Currently the drug therapy for MS includes the following:
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Corticosteroids - Side effects may include increased blood pressure, weight gain, high blood sugar and increased risk of infections etc.
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Glatiramer - Side effects may include flushing and shortness of breath after injection.
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Betainterferons – These beta-interferons can cause side effects, including liver damage.
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Natalizumab - Natalizumab is generally reserved for people who see no results from or can't tolerate other types of treatments. This is because Natalizumab increases the risk of progressive multifocal leukoencephalopathy — a brain infection that is usually fatal.
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Mitoxantrone - This immunosuppressant drug can be harmful to the heart, and it's associated with development of blood cancers like leukemia, so it's usually used only to treat severe, advanced multiple sclerosis.


Scientific Rationale
We recognize that the current drug therapy lacks specificity and targets all mature B cells leading to immunodeficiency which is highly undesirable.

At the heart of Transgene’s drug development for MS lies the recognition of two major proteins eliciting an immune response by auto-reactive B cells producing specific antibodies. These auto-reactive antibodies are known to cause demyelination of axon sheath. Therefore, our strategy revolves round targeting and eliminating the auto-reactive B cells thereby halting the progression of demyelination.



Progress
The scientists at Transgene have generated genetically engineered clones based on Transgene’s proprietary platform expressing specific fusion proteins that attack and eliminate those specific B cells while leaving the healthy B cells intact.

In-vitro studies are in progress to confirm the efficacy of the TBL 1108MS followed by in-vivo studies.
 
 
 
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