Adenoviruses are a large family of DNA viruses that infect humans and animals. They are relatively easy to manipulate by genetic engineering, they're stable, and infected cells express large amounts of the delivered gene product. Unlike retroviruses and adeno-associated viruses, Adenoviruses don't integrate their DNA into the host, which makes them less likely to cause cancer as a side effect - something that has been seen in gene therapy trials with the other delivery systems. This lack of integration is a problem for gene therapies that need long-term maintenance of the delivered gene, as is the case for genetic diseases where you want to fix lots of normal cells. But for cancer, this is not a problem. You don't care if p53 is stable in the cancer cells, because you expect p53 to kill them quickly. Unstable expression in the normal cells that also get infected is also OK; they already have their own good copies of p53.
Normal adenoviruses cause disease, but most adenoviral disease is relatively mild and most humans have already been exposed to adenoviruses. The disease-causing parts of the adenovirus can be removed by genetic engineering, and the adenoviruses can even be crippled so that they can only grow in the special cells in the lab. All these reasons led people to think that adenovirus vectors (gene delivery systems) would be safe and efficient - at least compared to the available alternatives.
So, Introgen had their anticancer magic bullet (p53) and their delivery system (modified adenovirus) back in the mid 1990s. By 1994, Introgen was starting Phase I clinical trials. The idea of p53-adenovirus anticancer gene therapy was so obviously good, the Chinese stole it! Science magazine wrote in 2006:
Introgen Therapeutics in Austin, Texas, for example, claims that SiBiono's Gendicine is similar to its own experimental product, a recombinant adenovirus containing the human p53 gene (rAd-p53).Gendicine beat Advexin to the punch in China, but Introgen still held the patents for the US and European markets. The silver lining was that Gendicine's Chinese approval in 2003 was another piece of evidence that Advexin would work.
Wei-Wei Zhang, president and CEO of San Diego-based GenWay Biotech, published the first paper on rAd-p53 while working at the University of Texas M. D. Anderson Cancer Center in Houston in 1994. He holds U.S. patents on the viral construct and related processes. M. D. Anderson negotiated a license with Introgen, which has spent more than $70 million to develop a product based on Zhang's rAd-p53, trademarked Advexin. It has been in clinical trials since 1994. The company's ongoing phase III trial using Advexin to treat head and neck cancer is under review for "accelerated approval" by FDA.
Introgen's 106-patient phase II trial in 2005 showed a 10% "tumor response rate," defined by at least 30% reduction in tumor size, in patients who received Advexin alone. Introgen Vice President Robert Sobol says phase III trials are going well.
Meanwhile, Introgen CEO David Nance claims that Gendicine is a "derivative" of his company's product. In an August 2006 filing with the U.S. Securities and Exchange Commission, Introgen claims that Gendicine infringes on a 1994 patent filed in China but concedes that "enforcement of patents in China is unpredictable, and we do not know if monetary damages could be recovered from SiBiono."
To be continued...