Expert Introduction:

Dr. Liu Jianghai, post-doctoral fellow of Canada Saskatchewan Therapeutic Antibody Resource, is founder, executive president and general manager of ABlink Biotech Co., Ltd. (hereinafter referred to as "Ablink"). In March 2016, Dr. Liu founded ABlink together with Dr. Ron Geyer, Director of Saskatchewan Therapeutic Antibody Resource in Canada. In 2017, ABlink successfully developed the new-generation "antibody phage display library" with independent intellectual property right, becoming China's first high-tech enterprise developing "chimeric antigen receptor T cells".

Dr. Liu Jianghai

At present, China's biological industry is facing historical development opportunities, brought by the policy support from the State, the international regulatory system introduced by the National Medical Products Administration, and the huge market potential unexplored. The penetration rate and usage rate of biomedicine are increasing among Chinese patients. As the domestic antibody research and development is gaining momentum, the public is increasingly aware of the importance of antibodies, reflected by a great number of enterprises pouring money in this field. For today's interview, we have invited Dr. Liu Jianghai, an expert in antibody library technology, to introduce the current situation of antibody drug industry, the key technologies and development prospects for antibody drug development, and the product portfolio of ABlink.

Introduction to the Development Process of Antibody Drugs and the Antibody Library Technology

The development process of antibody drugs mainly includes three major steps: discovery and verification of targets, discovery and verification of antibodies, and industrial production of antibody drugs. According to Dr. Liu, there are currently three mainstream technologies for antibody discovery: phage display library technology, transgenic mouse technology and B-cell sorting technology that has emerged in recent years.

Among them, the phage display library is the technology that inserts the DNA sequence of foreign protein or peptide into the appropriate position of phage coat protein structural gene, so that the exogenous gene can be expressed along with the expression of phage coat protein itself. Meanwhile, the foreign protein also can be shown in the surface of phage coat protein following the reassembly of phage. This technology won the Nobel Prize in Chemistry in October 2018. In fact, this technology originated in the 1980s. After more than 30 years of iterative development, it has now formed a more sound technology system. However, as the domestic research and development environment stands today, most enterprises are still using early technologies that have been phased out by the international market. The Toronto Recombinant Antibody Centre (TRAC) and the Saskatchewan Therapeutic Antibody Resource in Canada are currently world-renowned academic research institutions in antibody library technology. Before returning to China, Dr. Liu had been engaged in the research of antibody library technology at the Saskatchewan Therapeutic Antibody Resource for many years, so he is an expert in every way. When it comes to research and development enterprises of phage display library technology, Germany's MorphoSys AG is most well-known. In technology, it shares the same ultimate goal with Dr. Liu-founded ABlink of designing high-quality antibody libraries enabling easy antibody screening, but has different concepts, characteristics and advantages.

In addition, the final link of antibody discovery, industrial production, involves the construction of stably transformed cell lines after antibody discovery, and the amplification of production process, etc. In the domestic antibody drug industry chain, there is almost no upper industry, while the middle and lower industries have a quite early start, and are well-developed so far. Even some are able to jostle for a share in the international market, such as WuXi AppTec, a renowned CRO leader both at home and abroad. WuXi AppTec's CMC service that can solve the problems of production amplification after obtaining effective antibody sequences for antibody discovery enterprises not only has a good quality, but also is much cheaper than the European and American markets. At home, the majority of antibody drugs are generic ones without patent research and development costs, and the downstream industrialization process is mature and highly cost-efficient. That's why the price of domestic antibody drugs is lower than that of imported ones.

Two bottlenecks facing the development of antibody drugs

According to Dr. Liu, one bottleneck facing the development of domestic antibody drugs lies in the inability to make a breakthrough in the discovery of upstream innovative targets and the lack of advanced antibody discovery technology.

He believes that the discovery of innovative targets must be based on sound and strong basic discipline research. At present, there is no effort made, however, in this link in China. This is not a situation that can be changed by a single enterprise, scientific research institute or university. Instead, it entails strong policy guidance and support from the State by taking multiple-pronged measures in aspects from construction of basic disciplines, fostering of professional talent to cultivation of innovative target discovery enterprises. No doubt this will be a long process. Therefore, in the discovery of innovative targets, China cannot reach the international advanced level in the short term. But the positive is that in recent years, as a large number of overseas medical professionals return to start their own businesses at home, especially in the southeast coastal areas, some multinational partnerships and scientific research institutes at the forefront of international technology have begun to make some headway in this area, and gradually discovered some innovative targets, which indicates a good beginning.

Another bottleneck is how to use more advanced technologies to discover and verify new antibody sequences.

Over recent years, these well-trained "returnees" have injected fresh blood into the domestic research and development environment, which will advance the effort in antibody library technology, transgenic mouse technology and B-cell differentiation technology. The antibody discovery link involves many technical problems and relies heavily on the professional experience and new design concepts of research and development personnel. Therefore, professionals who have been engaged in relevant work for a long time abroad are able to make technological breakthroughs in this area.

About China's Antibody Drug Industry

As the most antibody enterprises in China are concentrated in the downstream of the industry chain, namely industrial production of antibodies, how to build stably transformed cell lines, how to amplify the process, how to improve production efficiency and other issues are of great importance. Compared with the pace of international development, the downstream of China's antibody drug industry has basically entered the fast lane of development. Moreover, in terms of clinical drug trials, due to the strict evaluation procedures and the limited number of patients, their clinical trials generally last eight to ten years in Europe and the United States. However, in China, because of the large population base and the sufficient patient data, coupled with the more and more simplified evaluation and approval procedures, the development and production cycles of antibody drugs have been sharply shortened. For example, Suzhou Innovent Biologics, a company ranked in the first echelon in the development of domestic PD-1 monoclonal antibody, launched its products at the beginning of this year after strict examination. From IND, Phase-II clinical trials to launch, it took only three years. Although it incurred plenty of doubt at that time, its clinical trials were conducted simultaneously in multiple centers where China's national conditions permit, thus greatly accelerating the acquisition of clinical trial data. In addition, the National Medical Products Administration continues to carry out reforms to develop a scientific and efficient approval process, and it also provides many preferable evaluation conditions to further accelerate the application and approval of new drugs.

In general, in terms of industrial production and clinical trials, either by relying on the already well-developed industrial advantages at home or by leveraging the convenience provided by the national policy reform, domestic antibody drugs have been finally provided with strong latecomer’s impetus to enter the market. In addition, more and more enterprises are inclined to purchase effective antibody sequences, while they themselves focus on subsequent work including process amplification, clinical trials as well as application and approval, so that antibody drugs can be launched as products to serve patients as soon as possible.

Enterprises striving for development are gradually reluctant to get stuck in downstream market activities forever. But making a rash foray into the field of antibody discovery means high cost. Therefore, such enterprises tend to set up research and development centers abroad, where the research and development atmosphere is more mature, team members are more professional and research and development efficiency is hence greatly increased. There are also some enterprises choosing to acquire upstream antibody discovery teams, such as those focusing on phage display library technology and transgenic mouse technology to make them antibody sequence discovery centers for their parent companies. However, there are very few domestic teams specializing in early antibody discovery, and these teams also prefer to maintain their own research and development independence, so there are fewer teams willing to be acquired. At present, downstream enterprises rely on the confirmed antibody sequences they purchased from abroad for transfer and transformation. But more and more early antibody discovery enterprises will start their strategic efforts in downstream production, no longer willing to transfer antibody varieties. Therefore, enterprises should make enough preparation as soon as possible to avoid putting themselves in a tough spot of having no access to antibody sequences.

The Development Plan of ABlink

Speaking of the future strategic plan of ABlink, Dr. Liu mentioned two important tasks. One is the discovery of new bio-macromolecule drugs, including monoclonal drugs, CAR-T/TCR-T drugs, polypeptide drugs, protein drugs, etc. to screen antibodies and provide antibody sequences and antibody varieties that have completed animal pharmacodynamic tests for enterprises. Another is the development service of monoclonal antibody testing reagents to provide products of this kind to third-party testing companies. At present, many inspection and testing companies have used ABlink's output technology to produce rabbit monoclonal antibody and mouse monoclonal antibody with good quality, high stability and low cost.

Large pharmaceutical enterprises and scientific research institutes are the main service targets of ABlink's discovery of bio-macromolecule drugs. ABlink uses its own antibody library to screen corresponding antibodies for the antigen protein or sequence provided by them. In the coming two years, ABlink will continue to focus on technical services, but it will also independently develop new drug varieties, hoping to launch them in two to three years. When asked about how to provide drug research and development technical services, whilst avoiding competition with clients, Dr. Liu said that once they accept the antibody varieties commissioned by clients, ABlink promises not to engage in the research and development and external services of the varieties within five years. Doing so can help establish a good credit system to carve out a good reputation in the industry for the company, and can also avoid waste of resources due to malicious artificial competition to live up to clients' favor and trust.

Currently, ABlink boasts a 12-person team which will expand to 20 to 30 people in the next two years, striving to develop complete antibody discovery capability from target identification to completion of key pre-clinical steps. These efforts can upgrade the depth of the company's technical services — providing verified antibody varieties whist offering opportunities for its future expansion to the downstream of antibody drugs. In terms of diversity, ABlink's antibody library is nearly 100-billion-level. By virtue of large capacity, high diversity and a substantial number of effective antibody sequences, it is a veritable 100-billion-level antibody library having no rival in China. To quote an old saying, the mechanic, who wishes to do his work well, must first sharpen his tools. While providing technical services, ABlink allocates special funds every year to upgrade its antibody library.

Dr. Liu's Experience of Starting a Business in Chengdu

Dr. Liu Jianghai comes from Pengzhou, Sichuan Province. Out of deep love for his hometown and fascinated by Chengdu's easy and comfortable lifestyle, he chose to start a business in Chengdu. Speaking of the early years when he started a business, Dr. Liu especially expressed his thanks to Chengdu Municipal People's Government for its policy support and to Tianfu Life Science Park for its favorable startup conditions. According to him, in an era defined by ever-changing technological advancement, continuous and effective communication with peers is essential if we want to stay at the forefront. And Tianfu Life Science Park is a perfect place for scientists with such social needs. In addition to ABlink, the Park is also home to a host of pharmaceutical companies like HitGen Inc., Biokin Pharmaceutical, ChemPartner, Genekey Biotech and WCFP. Located here, ABlink can not only learn from their development experience, but also make them their service clients, making ABlink get the best of both worlds. When it comes to the company's future development, he hopes that ABlink can make the most of its own competitive services and products to attract more attention and support from the outside world, whilst bringing the linkage effect brought by its antibody library technology strength into full play to attract more biopharmaceutical enterprises to Chengdu, thus developing local biopharmaceutical industry and creating a healthy industrial ecological circle together.

Now, ABlink has switched from "starting" mode to "expanding" mode. When talking about the problems encountered by the company in its accelerated development, Dr. Liu said that upgrading the laboratory environment is of great urgency for ABlink to prepare sites for its future animal pharmacodynamic test plan. At the same time, he also hopes that the government can guarantee effective implementation of a series of industrial support policies introduced, simplify and reduce some unnecessary duplicate application materials as far as possible and provide more "one-stop" service channels to support entrepreneurship, so as to put supporting services in place for Chengdu enterprises in a down-to-earth manner and make biomedical capital a fascinating calling card of Chengdu.

Dr. Liu Jianghai