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Story about Therapeutic Antibodies

The 1st topic: Discovery of POTELLIGENT®

Latent potential of antibody is sleekly extracted.
Dr. Kenya Shitara

In 2000, I had served as a senior researcher in the antibody research team that discovered "POTELLIGENT®" that is a technology supporting present Kyowa Hakko Kirin Co., Ltd.

Technology that expands the possibility of therapeutic antibodies

In antibody that removes foreign enemies such as cancer cells and viruses/bacteria invading the body (hereinafter referred to as "targets"), there are several mechanisms of action. Neutralizing activity in which antibody itself binds to a target and deactivates the target is representative example. Other than above, there is a mechanism called antibody-dependent cellular cytotoxicity (ADCC) in which antibody binding to a target induces effector cells that are attacker and attacks the target. POTELLIGENT® Technology refers to the technique that exponentially increases the ADCC activity more than ever before. We afford to say that this technique further expanded the possibility of therapeutic antibodies.

As a matter of fact, POTELLIGENT® Technology is a serendipitous discovery. At that time, there was no researcher who had specialized in the ADCC activity in our team. This is because attention was focused on neutralizing activity as a subject of research. Of course the ADCC activity had been measured but we did not have the mindset to increase the activity. At present, Kyowa Hakko Kirin is known as a specialist in antibody but we used to have actual achievement and know-how that could not even compete with the world's top level.

We arrived at the awareness from unexpected failure.

In the late 1990s, the antibody research team focused on research of a certain antibody. However, in the stage when we almost completed verification of efficacy and safety and began to implement clinical trial, the research met with a setback due to unexpected failure. Because we were in the stage that the team and others around us became to have a high expectation and were in hopes of implementing the first clinical trial using humanized antibody in the company, we were in major shock. The antibody prepared from rat cells in the early stage got good results but the activity decreased just after change in type of cells in order to move on to full-scale development. This was beyond the scope of the assumption.

However, when something that is inconsistent with the hypothesis happens, people sometimes learn something new. We had thoroughly examined what’s the difference from those of the past and why drug efficacy decreased. We did not turn up the difference even after we had examined thoroughly amino acid sequence of the antibody. As a result of detecting the cause point by point without quitting, however, the analysis group turned up that a sugar called fucose increased by change in the type of cells. Fucose is a part of sugar chain that is a composing element of antibody. Nobody thought a large difference like this occurred only by presence or absence of fucose. By this amazing discovery, we had developed the technology that exponentially increases the ADCC activity of antibodies by de-fucosylation and applied for a patent in 1999. This technology was named "potency/potential + intelligent = POTELLIGENT" Technology by being infused with the meaning that "latent potential of antibody is sleekly extracted". We think association between ADCC activity and fucose still had not been discovered only by accumulation of theories. Hypothesis, verification and unexpected failure gave us a lot of awareness.

"Magic Bullet" that is becoming a reality

In around 1984 when I entered the company, we had faced the first boom of biotechnology. Antibody had been called "Magic Bullet", everybody had believed that antibody can provide a cure for cancer and clinical trials had been actively implemented. However, the antibody that worked out well in the early research did not have the expected effect in human body. Almost all clinical trials ended up in failure and the fad had gradually passed. We were unstable at this time just as someone thought. Not only the research did not go well but also other major pharmaceutical manufacturers withdrew from therapeutic antibodies one right after the other. We sometimes wondered if we should just keep it up. I think all of us were concerned about that antibody really acts as a drug. Meanwhile, however, there was a positive sign. We saw a sign suggestive of that not mouse antibody but humanized antibody may have possibilities. We had a belief in the possibility and decided to continue the research.

Research and development of drugs take a considerably long time. And, the possibility of leading to actual development of new drugs is never high. It is said that for usual low molecule medicines, we have only an outside chance of moving on to new drug from research in the early stage. Even after entering clinical trial, only about 7% of the drugs are delivered to patients in actuality. As much as that, high level of efficacy and safety is a requirement for the modern medications.

POTELLIGENT® Technology that became advantage in development of therapeutic antibodies after a process of trial and error by many researchers including our team is made a benefit of our developing products and is becoming to translate into reality. We find our special delight in going smoothly because it is a difficult challenge. Now, we would like to obtain approval of a pharmaceutical product using the technique and to deliver it to patients as early as possible.

This content is identical to that delivered as web newsletter in the fiscal year of 2011.

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