November 1, 2008 (Vol. 28, No. 19)

ImmunoGenetix Applies Research Findings from University of Kansas Medical Center

At least 30 vaccines for HIV are in clinical trials to either prevent HIV infection or suppress the development of AIDS.

James Laufenberg, president and CEO of ImmunoGenetix Therapeutics, is working toward filing an IND for yet another HIV vaccine. Just two injections of his company’s therapeutic DNA vaccine reduces viral load, raises CD4+ counts, and prevents the progression to AIDS for up to four years in monkeys, he says.

If the vaccine works as well in people infected with HIV, they may be able to reduce or stop taking the expensive and cumbersome cocktail of drugs known as HAART (highly active antiretroviral therapy).

A personal experience underlies Laufenberg’s goal of marketing an immunotherapy for HIV. His younger brother died from AIDS in the 1990s before HAART became available. Laufenberg, a veteran of the pharmaceutical industry for 25 years, looked for a new business opportunity after retiring, and heard about a DNA vaccine for HIV being developed at the University of Kansas Medical Center. Laufenberg hopes to “not only build a company, but also to improve the way HIV is treated,” he says.

The field of HIV vaccines has been fraught with recent disappointments. On July 18, Anthony Fauci, director of the National Institute of Allergy and Infectious Disease (NIAID), cancelled plans for a clinical trial to test its preventive AIDS vaccine.

The vaccine contained the adenovirus-5 cold virus, which was implicated in the failure ten months earlier of a similar vaccine made by Merck & Co. That study was stopped early because the adenovirus-5 viral carrier was suspected of making some people more susceptible to HIV infection.

Fauci also mentioned that future studies of HIV vaccines should consider scrapping the ultimate goal of preventing disease, and instead aim to lower viral levels. “That’s our approach,” says Laufenberg. “Maybe some day we’ll figure out how to prevent the uptake of HIV, but that approach does not appear at hand in the near future.”

Human-Monkey Hybrid Vaccine

ImmunoGenetix’ lentiviral-based vaccine was created in the laboratory of the late Opendra “Bill” Narayan, D.V.M., Ph.D., at the Marion Merrell Dow laboratory of viral pathogenesis at the University of Kansas Medical Center. Dubbed GenePro™, the DNA construct blends monkey and human genes that give rise to HIV infections—six of the nine HIV genes in the vaccine code for HIV component proteins. The vaccine induces both an enhanced antibody and cellular immune response that inhibits viral replication and prevents the onset of AIDS in preclinical studies without the need for boosters or antiviral drug therapy.

GenePro is the lead DNA immunotherapeutic candidate at ImmunGenetix. The company also holds exclusive worldwide rights to several proprietary therapeutic candidates and supporting technologies invented in Dr. Narayan’s laboratory.

Several key HIV genes, such as integrase and reverse transcriptase, are intentionally missing from GenePro to insure that it does not incorporate into the host cell’s genome. The viral proteins generated also do not assemble into viral particles or cause infection. Although the HIV proteins made are not infectious, the body still recognizes them as foreign, and the immune system launches a robust cellular and antibody response. The viral proteins are made within muscle cells for several weeks, thereby mimicking viral replication and causing an extended immune stimulation.

The monkey, or simian, part of the DNA vaccine was developed by passing a pathogenic simian HIV (SHIV) virus through monkeys for five generations. The most pathogenic mutants were selected from each generation, resulting in a SHIV strain that triggers a high level of gene expression and protein production. In addition, the incorporation of a SIV promoter region (5’LTR) insures that the HIV proteins produced are properly processed, folded, and presented to the immune system.

Clinical Advantages

GenePro has been evaluated in preclinical models. In one of the most striking trials, 12 macaque monkeys received two intramuscular injections of the vaccine before challenged with the highly pathogenic SHIV 89.6P virus.

All 12 of the vaccinated macaques showed a rapid reduction in peak viral loads, and their CD4+ counts remained high. (Low CD4+ cell counts are a biomarker for disease progression.) All 12 macaques lived for two or more years, and the viral loads became undetectable over time.

In contrast, seven control macaques not pretreated with GenePro showed high viral loads and significant loss of CD4+ cells after exposure to the SHIV 89.6P virus. Four of the controls developed AIDS and died, and two more were at high risk for AIDS after two years.

Based on preclinical work, Laufenberg predicts that GenePro may work best in patients in the early stages of HIV who have low levels of HIV and high CD4+ counts. Once the immune system gears up to fight HIV, the DNA vaccine should limit viral replication and prevent progression to AIDS. A reduced dependency on HAART should follow.

Although the incidence and prevalence of AIDS is down sharply since the introduction of HAART, the complex drug regimen is expensive, inconvenient, and has substantial side effects. Preclinical trials suggest that GenePro may prevent the spread of HIV, too. “GenePro could especially benefit the 2.5 million children in the world with HIV to help them live healthier lives,” Laufenberg says.

Superior preclinical results are not the only factors working in GenePro’s favor. DNA vaccines, in genera, hold a number of advantages over competing recombinant protein and viral vector vaccines. DNA vaccines are easier and less expensive to make than recombinant protein or viral vector types.

Recombinant protein vaccines are typically cleared relatively quickly and do not trigger a strong enough cellular immune response to control HIV. Viral vector vaccines induce an immune response to both the non-HIV vector and HIV components, and the response to the vector may limit the response to the target antigens. Moreover, most protein and viral vector vaccines require refrigerated storage, whereas DNA vaccines can be stored at room temperature. This will make it easier to treat people infected with HIV worldwide with GenePro.

Laufenberg plans to hold a pre-IND meeting with the FDA by the end of the year. Currently, he is the company’s sole full-time employee and keeps costs down by contracting out technical services. Once Phase I trials start, the company will scale up to 12 full-time positions. When the efficacy of GenePro is proven, ImmunoGenetix will seek partners at larger pharmaceutical and biotechnology companies to advance its development.

“The promise is phenomenal,” says Laufenberg. “We can treat HIV, keep viral loads down and CD4+ counts high, and there’s less toxicity and less chance for drug resistance.”

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