In every cell in the human body is a mechanism that prepares it to commit suicide when the time is ripe. The moment a cell ceases to benefit the collective organism, becoming a burden instead, it receives a message that its time is up. The message comes as a protein or hormone that the body produces, which initiate a series of processes that will ultimately kill the cell in an environmentally friendly manner that barely leaves a mark.
This mechanism, called apoptosis, was discovered about 20 years ago. Many researchers were enthusiastic about the discovery - if this mechanism can liquidate cells, then it would be possible to use for the opposite purpose, to keep them alive. After a while, some researchers began to think about another and no less important potential use - killing undesirable cells. This is where Target-In ltd. comes in.
"The cell has two destruction," explains Target-In president and CEO Dr. Shai Yarkoni. "One mechanism is violent. When a cell is attacked by chemicals, radiation, or biological toxins, its membrane is affected, and the cell explodes and dies. The cell spills its contents into the surroundings, resulting in inflammation."
Apoptosis is much friendlier. "This is the cell's altruistic death. It shrinks, without losing its membrane. The cells internal parts disintegrate, and only after they become tiny and harmless particles, does the membrane crack, releasing the particles into the environment, which absorbs them," says Yarkoni.
Undesirable cells, or improper cell function, are responsible for some of the most severe diseases of the 21st century, including cancer and autoimmune diseases. In most cases today, cancer is treated by directly killing the affected cells by radiation or chemotherapy, which sometimes involve powerful side effects that frequently render their use not worthwhile. These treatments attack the whole body with almost the same intensity that they attack the affected cells. There has been a race in recent decades to find treatments that focus only on the cells that must be eliminated.
Antibodies are one such mechanism that has become a hot research and pharmaceutical development subject in recent years. Yarkoni and his partner, Target-In chief scientist Dr. Haya Lorberboum-Galski, started out in this area.
Every cell has many connection points, rather like biological locks. For a substance to act on a cell, it must fit these locks precisely; i.e. it has to be the right key.
As researchers begin to better understand cellular structure, they can create keys for each of the cell's locks. An antibody is a key that is precisely compatible to a certain type of cell, but instead of activating the cell, it is designed to sabotage it.
Yarkoni says that a huge amount of work has been carried out in recent years to build compatible keys for undesirable cells in the body. "Many locks have been discovered, and almost every company and laboratory is now working on suitable keys," he says.
These keys, called "monoclonal antibodies", constitute a $10 billion market. Nevertheless, even though these keys have been highly successful in terms of compatibility to cells, their ability to kill them without side effects has been less so.
The question of the day is: What substance has to be added to the material that can identify an undesirable cell, in order to kill it successfully? Various researchers have begun inserting various toxins or lethal proteins into cells, which leads almost directly to the next idea: instead of a toxin, it might be possible to insert in the antibody a substance to encourage apoptosis - a natural, environmentally friendly death without side effects.
This is exactly what Target-In does. "We've attached to the end of the antibody a substance that activates the cell's internal suicide mechanism. When the antibody (or any other "key" material) reaches the undesirable cell to which it has been directed, the substance is released and apoptosis begins. Since we activate a mechanism already present in the cell, the dosages necessary are very small."
Yarkoni cannot explain why no one thought of this before, except for the fact that apoptosis is a new research field, with a history of only 20 years. He says Target-In has registered the concept through five families of patents. "The link between the apoptosis-inducing substance and the antibody that directs it to its target has itself been patented," he says proudly.
Yarkoni began his professional carrier at Mamram (the IDF Central Data Processing Unit), but switched to medicine after his discharge. He studied at Hebrew University in Jerusalem, specializing in gynecology, in which he received his Ph.D. While working as a doctor, he decided to seek another Ph.D. in genetic engineering under Dr. Lorberboum-Galski. In 1999, Yarkoni entered the biotechnology industry, serving for four years as CTO in Collguard Biopharmaceuticals Ltd., a drug-development start-up. At Collguard, Yarkoni took a drug from the stage of animal testing to Phase II clinical trials in the US, UK, and Israel.
For the past 20 years, Lorberboum-Galski has specialized in immunotoxins, while serving as head of the Department of Biochemistry at Hebrew University. While she was overseeing Yarkoni's doctoral thesis, they would discuss possible developments in the field of antibodies. "Then, one day, light dawned," says Yarkoni. He got an idea, which he and Lorberboum-Galski developed into a series of products, which have proven effective in animal trials.
In addition to Yarkoni and Lorberboum-Galski, other top people at Target-In include director Dr. Avri Havron, a former CTO at Clal Biotechnology Industries Ltd. (CBI) and VP at Savient Pharmaceuticals Inc. (Nasdaq:SVNT) and InterPharm Laboratories; and science committee head Marcel Rosenzweig, a leading cancer researcher and former VP at Bristol-Myers Squibb Co. (NYSE:BMY), who Yarkoni says is responsible for most of the company's leadership in the cancer field.
"Globes": Which diseases can this patent treat?
Yarkoni "It can be used to treat any disease caused by a cell. If all goes well, we're talking about a company that could be as big as Teva Pharmaceutical Industries Ltd. (Nasdaq:TEVA; TASE:TEVA) in 10-15. Every company now developing an antibody for a particular purpose can add our apoptosis substance to make it effective, paying us royalties on the use.
"In addition, we're developing some of these mechanisms ourselves. One mechanism is anti-cancer that sits on a substance identified in Lorberboum-Galski's lab. We exploit the wide know-how in the field, which has already become general knowledge. Our models indicate that this substance might effectively treat half of existing cancers.
"Except for our breakthroughs, we're trying to be as un-innovative as possible, in order to ease the research process and regulatory procedures. Therefore, our second mechanism, intended to treat autoimmune diseases, uses a substance called Interleukin-2, which is already sold in the market specifically for these diseases. Interleukin-2 identifies T-cells. During a transplant, T-cells combat the implant, which it identifies as invasive tissue, and they develop many more Interleukin-2 receptors. We believe that our substance, Cytokine with an apoptosis additive, will be used as an additive for every transplant."
Will you try to develop this substance into production and sales?
"The plan is to reach Phase II clinical trials of the four substances we plan to develop in-house, and then seek a strategic partner or buyer for these activities. Since we're based on existing products, and because we can enjoy expedited licensing, we believe that we'll have revenue within five years - an astonishing speed for a biotechnology company."
Who are your investors?
"Hebrew University has invested $200,000, in addition to investment in registering our patents. We later joined an EU-financed consortium, from which we obtained an additional $250,000. With these resources, we're developing the first two molecules.
"We were somewhat disappointed by venture capital funds. Anyone who understands this subject - and there are very few funds that understand biotechnology, as most focus on medical devices and diagnostics - expressed great interest. But they all told us the same thing: 'It's too early for us. When you reach human clinical trials, call us.' We had hoped for a different response from the funds. Target-In is now displaying its products at the prestigious Tremplin Enterprises capital raising event, sponsored by the French Senate. At Tremplin, the best French start-ups meet 150 leading European investment houses. This year, the Israel Export and International Cooperation Institute managed to bring three Israeli companies to the event. They are the only non-French companies at the event, except for one Canadian company.
"Israel is a concept powerhouse, and that's how the world perceives it. We have no added value in development or manufacturing, but we're full of ideas."
How can more biotechnology companies be brought to advanced stages?
"2004 and 2005 were critical for Israeli biotechnology. Biotechnology General and InterPharm, two of the few advanced biotechnology companies active in Israel, closed down, leaving behind hundreds of experts, buildings and expensive equipment, which are not in use. Regrettably, the government is not providing funding to preserve activity on these infrastructures in the context of start-ups. Only a few hundred thousand dollars is needed, but the financing is not there. I personally proposed renting one floor for our company, but that, too, didn’t happen. Deputy Chief Scientist Dr. Shaul Freireich strongly supported the issue, but wasn’t able to pull it off for petty reasons. It's a great shame - they're going to sell the equipment as junk.
"Personally, I learned at Collguard that outsourcing is the best way to develop drugs. Israel's biotechnology infrastructure is problematic. It's very expensive to start building a company, so a changing management of infrastructures is needed. I buy most of my inputs, manufacture at another company, conduct trials in another, and the goal is to build a complex company with a team of managers, each of whom is an expert in his or her field; each one will be like a department. We're now considering opening an office for business development in the US or Europe."
Published by Globes [online], Israel business news - www.globes.co.il - on July 6, 2005