Background

Although researchers continue to expand our knowledge of the pathogenesis of HIV infection, the prospects for developing an effective, prophylactic, preventative vaccine seem more remote than ever.

Many experimental vaccines have been studied, and all have failed to achieve protective immunity.  Even in the case of a live-attenuated virus vaccine, one of the most effective strategies to achieve neutralizing immunity, protection against a challenge by a pathogenic, AIDS-causing virus disappears once the innocuous vaccine infection subsides. 

This dramatic improvement has not been without hardships and complications.  For example, the HAART cocktail requires the daily administration of multiple different drug types totaling over 20 pills per day.  In addition to the expense and inconvenience of committing to such a complicated drug dosing regimen, side effects can be substantial, and long-term problems with heart and kidney disease are starting to surface.  For example, it is estimated that approximately 10 percent of AIDS deaths are now due to protease inhibitor-induced heart disease.  Moreover, strains of HIV have emerged that are resisting anti-viral therapy, thus threatening to derail the effectiveness of HAART.

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Rationale

New strategies are emerging that seek to induce a patient’s immune system to more effectively fight HIV infection and reduce the dependency on anti-viral drugs.  In these approaches, patients must have a healthy immune system to respond to the immuno-stimulation therapy (e.g. low levels of HIV and high levels of CD4/CD8 cells).  The patient’s immune system is stimulated to attack and inhibit HIV replication.  Anti-viral therapy is then substantially reduced or eliminated and increased only when virus levels begin to rise.  An effective therapy will result in a substantially reduced requirement for anti-viral therapy, and along with it the high cost, inconvenience, and side effects of HAART.

Once the immune system has the upper hand on the infection, it is anticipated that a DNA-based immunotherapy will provide significant long term management of viral replication and prevent the development of AIDS with minimal assistance from anti-viral drugs.   It is also anticipated that this therapy will be less prone to deactivating HIV mutations, since the protective immunity is based on many antigenic determinants found on the produced HIV proteins.

DNA-based immuno-modulation approaches have a number of distinct advantages over killed virus, recombinant protein or live attenuated-virus strategies.  An intramuscular injected DNA construct that encodes for all but a few HIV genes will produce non-infectious HIV proteins, but not viable virus particles.  The DNA construct, however, will continue to produce viral proteins within a cell for several weeks, thereby mimicking a replicating virus.  This enhances the induced immune response over what could be achieved with a single injection of a killed virus or recombinant protein.  In addition, a recombinant protein or inactivated virus does not induce a cellular immune response, which has been shown to be important for controlling HIV.  A cellular response seems to emerge only when a patient makes the viral protein, as in the case of DNA therapies or attenuated virus vaccines.  ImmunoGenetix’s lead DNA immunotherapeutic candidate induces a significant disease-controlling cellular immune response in animal models.

Thus, a DNA-based immunotherapeutic has the safety of a killed virus or recombinant protein, and an immuno-stimulatory effect that is similar to a live-attenuated virus, but without the infection.  Since the injected DNA construct is eventually degraded and eliminated from the myocyte, repeated intramuscular injections of the DNA immunotherapeutic will be necessary to maintain an effective immune response against HIV.  The frequency of injections required will be established in clinical trials.  However, it is anticipated that the interval between injections is likely to be several months after an initial immune response is established.

The ImmunoGenetix lead product candidate GenePro™ (∆4SHIVku2), uses a DNA construct developed through animal passaging.  This approach generated a DNA construct with superior gene expression and subsequent non-infectious HIV protein production activity, which results in an enhanced immune response.  Unlike other DNA approaches, GenePro™ (∆4SHIVku2) stimulates both a cellular and antibody response that can control the replication of a deadly AIDS-causing virus in primate animal models without viral protein boosts and without anti-viral therapy.

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ImmunoGenetix has exclusive commercial rights to the following proprietary technologies developed at the Marion Merrell Dow Laboratory: (1) a patented pathogenic SHIV [SIV/HIV-1 (monkey-human) fusion virus] which gives rise to a preclinical model of HIV infection and AIDS in monkeys that closely mimics the disease in humans; and (2) DNA-based immunotherapeutic candidates that incorporate a proprietary DNA construct. This DNA construct increases gene expression and HIV protein production, and induces enhanced antibody and cellular immunes.  These immune responses effectively inhibit viral replication and prevent the onset of AIDS in animal studies without viral protein boosts or the use of anti-viral drug therapy.

Because several genes from HIV are deleted, GenePro™ (∆4SHIVku2) does not incorporate into the host cell’s genome, and the viral proteins that are produced are unable to assemble into viral particles.  These HIV proteins are not infectious in any way, however, they are recognized by the body’s immune system as an infection, and a significant cellular and humoral immunological response develops.   Unlike protein-adjuvant vaccines, the viral proteins in DNA-based therapies are produced within myocytes for a period estimated to be several weeks.  This longer exposure results in a more potent stimulation of the immune system, including a cell-based immune response, which is very difficult to induce with protein-based adjuvant vaccines.

 

The Company has entered into a license agreement in cooperation with the University of Kansas Medical Center Research Institute for the rights to the gene-related DNA therapeutic technology developed in Dr. Narayan’s laboratories. Under the terms of the license, the Company receives exclusive worldwide rights to develop and commercialize the technologies embodied in the following patents, in exchange for equity and royalties.