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.

The key obstacle in this effort stems from the fact that HIV targets the cells responsible for establishing and maintaining immunity.  A rapidly developing HIV infection can quickly destroy the immune cells required to mount an immunological response.  In addition, if a level of immunity is established, it can be eliminated when the virus attacks immunological memory cells, thereby destroying the cells that provide for long-term immunity.

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.

Although protective immunity against HIV infection does not seem possible at this time, the prospects for keeping an HIV infection at bay and preventing the development of AIDS has improved substantially.  Anti-viral therapies have completely changed the prognosis for HIV infected patients.  The incidence and prevalence of AIDS is down sharply since the introduction of the HAART cocktail (Highly Active Anti-Retroviral Therapy).

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.  IGXBio’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 themyocyte, 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 IGXBio 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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Technology Overview

IGXBio 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 proprietary DNA construct used in GenePro® (∆4SHIVku2) is derived from a pathogenic SHIV virus developed for use as an AIDS producing virus for evaluating the efficacy of prophylactic and therapeutic vaccine candidates.  This pathogenic SHIV was developed by passaging the initial SHIV through monkeys for five generations and selecting from each generation the mutated forms of SHIV that are most pathogenic.  This protocol generated an extremely pathogenic SHIV virus, which exhibits a high level of gene expression and protein production activity.  A corresponding DNA sequence from the pathogenic SHIV was developed and used as a backbone construct in designing DNA immunotherapeutic candidates and resulted in a superior gene-expressing and protein-producing DNA immunotherapeutic construct.  This DNA construct encodes for 6 of the 9 HIV genes, and does not incorporate into the cell genome.  The HIV proteins that are produced are unable to assemble into viral particles, thereby making the DNA construct completely non-infectious.  However, by using a DNA sequence that corresponds to the pathogenic SHIV backbone, higher levels of gene expression and protein production are achieved, thereby inducing a more robust immunological response.  Two intramuscular injections of this therapeutic agent in macaque monkeys resulted in the inducement of a cellular and humoral immune response that controlled an AIDS producing virus.  This disease controlling immune response was accomplished without the use of HIV viral protein boosts, which are necessary with other DNA immunotherapeutic approaches.

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Intellectual Property

IGXBio maintains a broad and diverse portfolio of issued patents (7) and applications (10) that cover all of its chemical series. Currently, the GenePro® vaccine composition is supported by more than sixteen U.S. and foreign patents and applications. If necessary in order to ensure protection of the compounds of highest interest, IGXBio will file additional applications. IGXBio’s general patenting strategy includes filing for protection in all of the major international markets. IGXBio has an exclusive worldwide license with the University of Kansas (KUCTC).

App Type File Date Serial No. Subject Matter Approximate Expiration Date
Patent Family: Second Generation DNA Vaccine Compositions and Methods (goat promoter)
US
Provisional
2/21/2012 61/601,322 General
DNA vaccine composition and methods comprising CAEV promoter and enhanced
safety
2/21/2032
Patent Family: DNA Vaccine Compositions and Methods
US
Utility
09/15/2004 Patent
No. 7,488,485 (Issued 02/10/2009)
SEQ.
ID. NO. 1 – sequence of DNA vaccine construct
8/13/2025*
o US Cont. 02/09/2009 12/368,151
(Published 09/17/2009)
Patent
No. 8,003,113 (Issued 08/23/2011)
General
DNA vaccine composition
9/15/2024
o US – DIV 07/18/2011 13/185,148 General
DNA vaccine composition including modifications to the construct sequence and
pharmaceutical compositions
Pending;
9/15/2024
o US – DIV 07/18/2011 13/185,164 General
DNA vaccine composition regulated by the CAEV goat promoter
Pending;
9/15/2024
o US – DIV 07/18/2011 13/185,158 Methods
of treating HIV/AIDS by administration of GenePro® DNA vaccine
Pending;
9/15/2024
PCT 09/16/2004 PCT/US2004/030512
(WO2005/027844 – Published 03/31/2005)
DNA
Vaccine Compositions and Methods
 
o Europe 09/16/2004 04784389.1
(Published 05/17/2006)
DNA
Vaccine Compositions and Methods of Use
Pending;
 9/16/2024
o Brazil 09/16/2004 PI0414442-2
(Published 11/14/2006)
DNA
Vaccine Compositions and Methods of Use
Pending;
9/16/2024
o Mexico 09/16/2004 PA/a/2006/002993
(Issued 11/17/2009)
DNA
Vaccine Compositions and Methods of Use
9/16/2024
o South Africa 09/16/2004 2006/3044
(Issued 07/25/2007)
DNA
Vaccine Compositions and Methods of Use
9/16/2024
o New Zealand 09/16/2004 545954
(Issued 08/13/2009)
DNA
Vaccine Compositions and Methods of Use
9/16/2024
o Australia 09/16/2004 2004273965
(Issued 12/09/2010)
DNA
Vaccine Compositions and Methods of Use
9/16/2024
o Japan 09/16/2004 2006-527060
(Published 03/15/2007)
DNA
Vaccine Compositions and Methods of Use
Pending;
9/16/2024
o Canada 09/16/2004 2,538,840
(Published 03/31/2005)
DNA
Vaccine Compositions and Methods of Use
Pending;
9/16/2004
o Israel 09/16/2004 174325
(Published 03/31/2005)
DNA
Vaccine Compositions and Methods of Use
Pending;
9/16/2004
Patent Family: GenePro® combination with inhibitors of Interluekin 4
US
Utility
11/15/2005 Patent
No. 7,585,675 (Issued 09/08/2009)
Inhibition
of HIV and SHIV Replication with Inhibitors of IL-4
1/2/2026*
o US Cont. 06/10/2009 12/481,904
(Published 11/18/2010)
Inhibition
of HIV and SHIV Replication with Inhibitors of IL-4
Pending;
11/15/2025

Abandoned applications
US
Utility
05/16/1995 Patent
No. 5,849,994 (Issued 12/15/1998)
Animal
Model for HIV-1 Induced Disease
Abandoned
(12/15/2015)
US
Utility
02/23/2006 11/360,957
(Abandoned)
HIV
DNA Vaccine
Abandoned
US
Utility
10/24/2002 10/279,992
(Abandoned)
HIV
Vaccine and Method of Use
Abandoned
* Patent Term Adjustment (PTA) issued by US Patent Office (PTO) that extends patent term due to PTO deficiencies.

The Company will rigorously protect its patent position and license related patent technology as required.

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