Admunex, a New HBC Spin-off, Has Eight Patents in the Works

The latest HBC spin-off company, Admunex Therapeutics, Inc., arose in the spring of 2001 as a practical answer to a good problem: Patents had piled up on founder Teruna Siahaan's desk. The KU Associate Professor of Pharmaceutical Chemistry and now Admunex President said he didn't have any intention of starting a business on his own.

"My colleagues just started noticing how many patents I had in the works." While talking with Siahaan about his discoveries, Roger Rajewski, acting director of the Center for Drug Delivery Research, and Osborne Wong, president and co-founder of ProQuest Pharmaceuticals, Inc., another HBC spin-off, asked him a pointed question: "Who's licensing all these patents?" Siahaan's answer of "nobody" set the Admunex wheels in motion.

"I think the time was right," Siahaan said. "It's good for Kansas and KU. At least somebody is pushing me to get discoveries licensed. Those of us passionate about the science would obviously like to see things get to the market, but we aren't in a position to do it ourselves."

Admunex is exploring the clinical potential of three major areas of Siahaan's research and has already submitted eight patents within them. One major discovery involves the identification of a specific receptor on T-cells which internalize its ligand upon activation. Though scientists have long known about this receptor in T-cells, no one had shown that it could internalize its ligand. Admunex will conjugate this ligand to drugs to ensure they target only activated T-cells, which are implicated in autoimmune disorders. Thus, this technology will increase the selectivity and lower the toxicity of the drugs. "We have already shown that this technology works in an animal model," said Siahaan.

Signalling of T-cells

In a second major area of research, Siahaan says that there are two necessary signals (Signal-1 and Signal-2) to activate a subpopulation of T-cells that cause them to attack the body during an autoimmune disease such as rheumatoid arthritis, lupus, psoriasis, or diabetes. Siahaan explained, "For T-cell activation, these two signals form a synapse that most resembles a doughnut. First the two signal molecules are spread all over T-cells, but when T-cells find the antigen presenting the cell for activation these molecules come together to form a doughnutlike synapse. Signal-1 tries to move to the center and Signal-2 tries to move to the outside of the doughnut. In our early studies, we've demonstrated that if you block the adhesion signal (Signal-2), the T-cells will not be activated. We discovered peptides that block the adhesion signal and suppress T-cell activation."

Since, Siahaan discovered that Signal-1 and Signal-2 are interdependent, he knew that if he could simultaneously control both signals, he could prevent a specific sub-population of T-cells from activating and attacking the body. He discovered molecules that prevent these two signals from crossing each other to form the synapse. These new molecules are more selective in inhibiting the activation of a specific subpopulation of T-cells than the adhesion signal inhibitors he had previously discovered. This technology can be applied to enhance immuno-tolerance in people with a genetic predisposition for certain autoimmune diseases. Because this technology is applied to the basic mechanisms of the immune response, it can be used to solve a broad variety of autoimmune disorders. Right now, Siahaan and researchers in his lab are focusing this research on developing a treatment for diabetes.

The third major area of Siahaan's research involves cell adhesion molecules in the intercellular junctions. These molecules are important in maintaining the integrity of the blood-brain barrier and the intestinal mucosa, and thus can prevent the body from absorbing large hydrophilic drugs composed of peptides and proteins. The intercellular junction is made up of E-cadherin proteins that basically function as a zipper.

Controlling the Zipper

Siahaan has found molecules that can modulate this "zipper" without opening the junction entirely, a discovery that could revolutionize drug delivery through the blood-brain barrier and the intestinal mucosa. These molecules can increase the porosity of the intercellular junction without destroying it entirely, and thus, they can enhance the delivery of peptides and proteins that previously could not cross the biological barriers.

"Many researchers had focused on delivering drugs through these barriers," Siahaan said. "But they had never really tackled the problem in a systematic way. We got where we are today by asking some fundamental and mechanistic questions: If drugs won't go through the junction, then why not? What's in the junction? How does it work? What is this "zipper" mechanism?"

An organic chemist, Siahaan did postdoctoral research at UC-Santa Barbara working with cyclopeptide antibiotics. From there he moved to the La Jolla Cancer Research Foundation (currently Burnham Institute) as head of its protein chemistry laboratory. During this time, he set up a peptide/protein synthesis and analysis laboratory and developed a passion for cell biology, specifically cell-to-cell and cell-to-matrix adhesions. At La Jolla, he developed cyclic peptides for anti-metastatic and anti-thrombic agents based on the inhibition of the cell adhesion process. From there he went to a pharmaceutical company Sterling-Winthrop, where he developed enzyme inhibitors to treat rheumatoid arthritis and cancers. While at Sterling-Winthrop, he began research into inhibiting T-cell activation using adhesion molecules. In 1991, he began developing his research program at the University of Kansas.

Siahaan is excited about the clinical potential of the patents that Admunex is licensing. "Our short-term goal is to develop drugs that can target a specific receptor and get some investors and/or collaborators interested. We've already shown that certain drugs work in several animal models. I would like to see Admunex formulate some of these drugs, so they could be put into the hands of partner companies and go into clinical trials."

Still in the preliminary stages as a business, Admunex is staffed by its founders. Siahaan and his co-founders realize that to do things right, both from a scientific and business perspective, takes long hours, hard work and patience. "We didn't develop these technologies overnight. Much of the thinking behind them has taken more than a decade to unfold. We want to make sure we do a thorough job on the business side as well. I'm happy to say we're not going to make empty promises with what we can do. Right now, we're looking at other companies and trying to distinguish ourselves from them; we're defining what we can offer that others cannot. It's an exciting time."