Dr. Hiroyuki Naito
◆Keys to success in the new technology DXd-ADC - what do you think were the driving forces behind innovation?
Dr. Naito: As a key to the success of the new technology DXd-ADC, we newly designed DXd, an effective and optimal payload, based on the Compound DX, and engineered and developed a new linker to separate this DXd. This innovation should be attributed to our ability to value previous data, carefully analyze both strong and weak points, imagine and design a possible drug, and creatively embody the design. Daiichi Sankyo had once conducted research on Compound DX, which boasts of superior pharmacological activity, and research on the drug delivery system of a polymer complex using the Compound DX. Unfortunately, the research results did not turn into a product and could be considered to be a failure. Nevertheless, our team carefully handled the previous data, thoroughly examined each good and bad point, and added fresh elements to it. The process facilitated its application and helped develop extremely effective drug linkers, leading to the DXd-ADC. Research on antibodies or chemotherapeutic agents may not work out well, but our members, specializing in various fields, made use of each other’s expertise and integrated technologies at an appropriate time—this must be a key point for our success. I also think this is a great thing about collaborative work and a critical point that stimulates innovation.
Dr. Ogitani: As a researcher engaged in evaluating pharmacological activities, I value two things: screening to identify and select a possibly useful drug from a list of candidates; and maximizing the drug’s value, which involves the process of collecting meaningful nonclinical data, sharing them with members in the clinical development team, and incorporating the results into designs for actual clinical trials. When developing this ADC, we first proposed the idea or a hypothesis, “This drug should be effective for a particular class of patients for such and such scientific reasons,” and obtained useful data in the verification process. As a result, the application was expanded to a larger number of patient groups, leading to major innovation. In charge of candidate drug discovery, Naito and Nakada held constant discussions with Abe and myself, who were engaged in evaluation. We then gave them feedback on the evaluation results and proposed what we should do next. This succession of procedures turned out to get done quite speedily, contributing to our success. We understand that it is important to present not just a hypothesis or theory but also data that endorse it. So, even when we persuaded senior researchers, we made a tenacious effort to collect a substantial amount of data.
Mr. Nakata: “When you need to be tenacious and persistent, you must be”—this is an important thought. ADC technology development requires a great deal of tenacity for repeatedly demonstrating the effects of candidate chemical compounds using in vivo animal models. Since we had various candidate linkers, a key for ADC technology, we explored all the possibilities, tested all candidates, and discussed the results before determining the direction instead of jumping to a conclusion. No matter how challenging the tasks were, I took them as my personal responsibility and thoroughly enjoyed developing solutions for each of them through research.
Dr. Abe: We, regardless of our age or position, said whatever we wanted to, proposed hypotheses, conducted experiments, and made decisions based on the data. Instead of deciding everything from a top-down approach, our team took an “empirical approach” that allowed us to discuss thoroughly, make a “working hypothesis,” verify it through an experimentation, and determine if it was worthwhile based on data.
Dr. Agatsuma: Researchers who fully connect with each other can work out high-quality experiment plans and produce meaningful data, stimulating heated discussions and encouraging more proposals and trials. This happened repeatedly, enabling us to determine if we were on the right track quickly and decide which direction we should take for a data-driven approach.
Mr. Takashi Nakada
◆What was a breakthrough?
Dr. Abe: As a member of this team, I never feared that the research would fail and meet a premature end. When we decided to go with the DNA topoisomerase I inhibitor, we welcomed Naito, who had more knowledge of chemical synthesis than any of us and helped us work even more smoothly. We achieved a breakthrough in the development of drug linkers, a key for ADC technology, through repeated attempts, leading to the discovery of a new drug linker technology.
Dr. Ogitani: It was shortly after I joined the company and had little experience in drug discovery. So when I evaluated a prospective drug linker, I concluded right away that, “This should work.” But I was devastated when that drug linker was later left out of a list of candidates. Shortly after, the chemical synthesis group comprising Naito and Nakada brought a spate of new ideas and helped us recover from the setback. I was impressed with our company’s chemical synthesis team, and I clearly remember that feeling.
Mr. Nakada: The first compound that disappointed Ogitani was one that I had provided him. But I did not feel any crisis, as I was aware that Naito was already working on developing another compound. I was also confident that our team would overcome any challenge.
Dr. Naito: In chemical synthesis, researchers create something completely new and take it as some sort of a “game” They develop drugs by doing what they want to—in my opinion, there is no other job as enjoyable as medicinal chemistry research. I guess medicinal chemists face setbacks now and then but grow afterward. Even when Ogitani faces difficulty, I can look at the situation from a different angle and think I have been given a chance for a breakthrough. Medicinal chemists can design and create compounds; that is how we enjoyed the research. I do not believe that the project ever reached a deadlock, and I now have a sense of achievement for being able to do what we had hoped to with the project ending as a success. In that sense, our success story might be slightly different from other popular ones, wherein the protagonists experience difficulties and are anxious until they achieve a breakthrough.
Towards Future Drug Discovery
A trophy of the award
◆New drug discovery modalities—where is Japan’s pharmaceutical industry heading?
Dr. Agatsuma: Japanese companies, which I believe are good at crafting and manufacturing, are proving successful in producing biopharmaceuticals, which is a major advance for them. This market is yet to be saturated and offers possibilities for various applications and the development of new drugs. Through developing our DXd-ADC technology, our company broadened its experiences in research processes and new technology platforms. This experience allows us to explore the possibility of ADCs loaded with other medical agents. Taking advantage of our strength, we hope to engage in research and tasks that contribute to patients. Also, since ADCs are a technology that delivers drugs specifically to targetable cells, it is likely to be applied to treatments for diseases other than just cancers.
Dr. Naito: In a graying society, the working population will continue to decline, and technological advancement is expected to pick up the pace to compensate for labor scarcity. In the field of drug discovery, collaboration with artificial intelligence (AI) has gained momentum in recent years. AI and IT can be key areas in drug discovery in the future.
Mr. Nakata: When we talk about contract development and manufacturing organizations (CDMO), the fact is Japanese drug makers are importing most of their reagents and materials from overseas. I am concerned about this, as it may undermine the continuity of their research and development and would instead stress the need to produce biopharmaceuticals from domestic materials.
Dr. Agatsuma: Recently, it has come to light that Japanese companies are having trouble procuring from overseas various parts and materials for industrial products, such as semiconductors. Likewise, the pharmaceutical industry is facing restrictions in procuring a diverse range of materials and components. Sharing functions efficiently on a global scale might be beneficial, but the procurement route could easily fall apart if parts of the world become politically unstable. If Japan aims to develop bio-business as one of its core industries, I recommend that related reagents and materials be managed comprehensively.
Our company has a history of more than a century and its research laboratories accepts graduates with outstanding educational qualifications. We need to educate them further so they can design research that benefits society, and our research center serves as their training hall. Scientists should be able to exchange their opinions freely. They must stimulate each other and become drug discovery researchers in this hall. They should continue to enhance their abilities and join forces to achieve research results. The achievement as a team generates a new task of contributing to many patients worldwide and could even develop into an influential product supporting Japan’s overall industry structure. It is ideal for offering to potential new hires a research organization that assures researchers that they can strengthen their skills and contribute to the world. Young people who enter our company as prospective innovators become actual innovators and play their part in an ecosystem that contributes to the world—this would be the best social contribution of our company. It might sound ambitious, but this is what I hope for our company.
* Antibody-drug conjugate (ADC): An antibody and drug (small molecule compound) connected by a linker to form a medication. The antibody connects with the targeted gene that causes cancer to deliver the drug directly to the cancer cells, thereby maximizing the anticancer effect while minimizing the body’s overall exposure to the drug.