Recently, Sanyou Biopharmaceuticals officially launched its independently developed Super-Trillion Antibody Libraries (STAL), and the concomitant innovative antibody drug discovery platform. Established by Sanyou after seven years of continuous innovation and independent R&D, the STAL antibody drug discovery platform represents a significant breakthrough over the previous generation of the sub-trillion innovative antibody discovery platforms.
Xie Yijun interviewed Dr. Guojun Lang, the founder and CEO of Sanyou, to learn more about the story behind the platform.
A vast resource of antibodies built up in 7 years
In 2015, Dr. Lang founded Sanyou Biopharmaceuticals, which seemed to be spontaneous to him.
At that time, he had been working in Henlius, an affiliate to Fosun Pharma specialized in R&D of antibody drugs, for several years. Around 2012, he built an antibody library of 10^10 (10 billion) capacity and led the team of Innovative R&D Department and Biologics Quality Control Department to participate in the R&D of more than ten antibody drugs. By the time he left Henlius, nearly half of those drugs had been filed for IND, and some had entered the clinic trails. As of now, five of them have been launched onto the market.
Dr. Lang then worked for another company for a short period as the head of product and marketing. "I was thinking it was time to put my ideas into actions." The first idea is to further develop and improve the technologies he mastered, so as to establish a platform that serves more pharmaceutical enterprises and thus have the opportunity to benefit more patients; on the other side, he hoped "to establish a company that creates superior values for the society". In order to carry out these ideas, he decided to start his own business.
"There were a lot of requirements for drug innovation from companies of my friends in the community, and our team had marketing experiences. Therefore we were sure we could make ends meet." With the technology, contracts, and people willing to join, Dr. Lang, together with two friends, founded Sanyou Biopharmaceuticals.
“The team of three in the first year of establishment grew to 10 members in the second year, 27 in the third year, 50 in the fourth year.” He clearly counted the number of staffs in every step of Sanyou's development.
Likewise, he is very familiar with Sanyou's LOGO. "It's like antibodies," Dr. Lang explained, "The tiny leaf-like elements on each antibody are pills. Those elements are a bit different from traditional antibodies, which represents our desire to innovate." The LOGO consists of three "innovative antibodies" in three different colors. "Three" represents "San" in "Sanyou", and "San" is "three" in Chinese, According to traditional Chinese philosophy "Three produced all things".
There is a circle under the three "antibodies". "It's like a big pool, as big as the sea, which represents the library. This library can generate a wide variety of antibodies to meet the drug discovery requirements."
The three "antibodies" also look like three people with their hands up and holding. "This represents our desire to open our hearts to the world and advance hand in hand with everyone." He explained the vision of Sanyou starting with its LOGO, "We want to deliver with the best quality, highest speed and top cost-efficiency, which is the core philosophy of Sanyou."
As Dr. Lang envisaged, Sanyou Biopharmaceuticals has established three generations of distinct antibody libraries, from which dozens of antibody drug projects were delivered.
From 2015 to 2016, Sanyou provided CRO services with its 10-billion-level antibody libraries and the first mouse immunization library in the Chinese market. At that time, Sanyou had established its independently developed phage display vector system and completed the design of synthetic and semi-synthetic antibody libraries.
In 2018, Sanyou launched the first sub-trillion human antibody library, as well as the naive single-domain library and immunization library, which provide comprehensive solutions for human, mouse, and alpaca antibodies covering the R&D of almost all varieties of antibody drugs at that time.
At the beginning of 2019, Sanyou initiated its plan for the construction of trillion-level antibody libraries. The first trillion-level antibody library was actually completed in December 2020, but what Sanyou planned to establish was a series of trillion-level libraries, rather than only one trillion antibody library.
"Now we have five trillion-level antibody libraries, with a large library capacity of seven trillion in total." After 7 years of upgrading for three generations, the property and performance of Sanyou's super-trillion antibody libraries are showing international advantages.
There is still more.
Highly-efficient discovery of lead antibodies with super-trillion libraries and high-throughput screening
At present, Sanyou has completed 5 trillion-level antibody libraries, i.e., fully human recombinant antibody library, fully human semi-synthetic antibody library, humanized 2C/4C single domain antibody libraries, and fully human common light chain antibody library.
Each of these libraries has its own characteristics. For example, the fully human recombinant antibody library is designed by recombination of antibody nucleotides from human B cells, to maintain natural sequences and improve drug developability; the fully human semi-synthetic antibody library is also derived from natural sequences, supplemented by molecular engineering designs to enhance the diversity; the degree of humanness for the antibody framework of the two humanized single domain antibody libraries is as high as 98%, with no need for further humanization; the common light chain antibody library is particularly suitable for the generation of bi-specific antibodies.
These libraries together can achieve full coverage of the antibody formats, such as fully human antibody, single-domain antibody, bi-specific antibody and mouse monoclonal antibody.
"These antibody libraries have been gradually established from the accumulation of the background technologies, conceptual design, to library constructions step by step." There are also four trillion-level libraries under construction according to Sanyou's plan, including trillion-level AC miniaturized protein library, trillion-level AF miniaturized protein library, trillion-level functional protein fusion antibody library, and trillion-level cyclic polypeptide library. The capacity of the 9 super-trillion libraries will be more than 10 trillion in total.
Screening with such large antibody libraries is a challenge. In order to facilitate screening, Sanyou effectively integrated technologies of phage display antibody libraries and protein expression by mammalian cells, and established an automated, high-throughput, and refined one-stop screening platform. After three years of refining, Sanyou Biopharmaceuticals has established an automatic R&D system to achieve highly efficient screening.
Phage display technology is one of the three mainstream technologies for antibody generation which was awarded for the Nobel Prize in Chemistry in 2018. Phage display technology has been verified by more than 10 commercially launched antibody drugs, including adalimumab, the top-sales medicine with annual sales of more than $20 billion, and Tremfya, known as the "best new drug for psoriasis".
The current global representative enterprises of the phage display technology include Cambridge Antibody Technology (CAT), which was acquired by Astrazeneca in 2006; Dyax, which was acquired by Shire, an UK pharmaceutical giant, in 2015; Morphosys, a Nasdaq-listed company that has not been acquired by any pharmaceutical company, developed aforementioned Tremfya in partnership with JNJ, and has converted into a biotechnology company.
Compared to hybridoma, another mainstream technology, phage display library enables high throughput and extremely large capacity. The capacity of mouse immune antibody library for hybridomas is up to 10^6 (million), while that of the phage display can be 10^10 to 10^11. For example, CAT and Dyax have a library capacity of 10^10 (10 billion), Morphosys has a library capacity of 10^11 (sub-trillion), while Sanyou achieved 7×10^12 (trillion).
In addition to the large library capacity, screening speed is another advantage. It is difficult to screen cells with the hybridoma technique. For example, it takes 10,000 plates to screen ten billion antibodies. "It's not practical in the real labs," said Dr. Lang. With phage display, on the other hand, the cells are fixed on a plate, allowing the phages to flow through, non-binders to be washed away, and the binding antibodies to remain. "It only takes a plate or a tube to do that, so it's particularly suitable for screenings where you have to use cells instead of unavailable protein antigens." In comparison, the screening takes 5 to 6 months for hybridoma, while phage display takes only 5 to 6 weeks, or as short as 16 days according to the best record of Sanyou.
That antibody was developed in 2020 for the treatment of COVID-19, and it took us only 16 days from the antigen protein to the generation of the eukaryotic expressed lead antibody, which was later transferred to Henlius. In October of that year, that monoclonal antibody obtained IND approval by the FDA.
A large number of lead antibodies can be quickly obtained from the ultra-large antibody libraries and highly-efficient high-throughput screening. "More than 2,000 lead antibodies can be obtained from these libraries, which guarantees much higher success rate of the drug R&D," said Dr. Lang with confidence.
High expression + high purity + high affinity = high developability
Having access to lead antibodies that have better drug developability is of great significance to clients. Phage display technology also has its unique advantages in this respect.
For the mouse immunization of hybridoma, since mice have many antigens, only some antigens or epitopes with strong immunogenicity will continuously stimulate the mice to produce antibodies after immunization, while other antigens or epitopes with weak immunogenicity could rarely do that. This results in poor immune effect of some antigens, limited coverage of epitopes, lack of good functional candidate antibodies, or insufficient in the candidate functional diversity.
Phage display, as an in vitro technology, can generate antibodies to cover most of the epitopes. Therefore, phage display can overcome the above drawbacks of the hybridoma technology.
"In addition, our libraries are designed based on the amino acid distribution of natural antibodies, which is natural or similar to the natural sequences with good drug properties and developability," said Dr. Lang.
Sanyou had conducted statistical analysis on more than 600 antibodies screened from super-trillion antibody libraries. The data showed that the transient expression level of 50% monoclonal antibodies was over 100 μg/mL, and the expression level of 75% nanobodies was over 300 μg /mL, indicating high expression level of those antibodies; 61% of the antibodies had affinity higher than 10-9M, and 14% of them higher than 10-10M, meeting the requirements of drug screening.
Sanyou had also carried out statistics on the SEC results of 1,982 antibodies screened from the super-trillion antibody libraries, among which 1,599 antibodies (81%) had a purity of more than 90%, and 1,441 ones (73%) more than 95%, proving that high proportion of the antibodies from the super-trillion antibody libraries meet the purity requirements for antibody drugs.
In addition to the monoclonal antibody drug mentioned above, Sanyou also developed a bispecific antibody drug for COVID-19 in collaboration with Liferiver, and Boehringer Ingelheim (BI) was in charge of the process optimization and manufacturing services. Although the project was delayed later due to the pandemic and changing market environment, the pre-clinical research and development have been completed and the pre-IND filing was accomplished in China and the United States, which reflects the developability of the antibody drug. This is an antibody drug for COVID-19 treatment developed by the Sanyou R&D team, as well as an advanced bispecific antibody drug in this field.
Researches related to the above COVID-19 antibody drugs have also been published in prestigious journals such as Science, Cell Research, and Cell Discovery.
Sanyou also collaborated with Dragon Boat Biopharmaceutical to develop antibodies targeting CLDN18.2.
The study on targeted therapy of the claudin family has attracted extensive attention, especially the application of targeted CLDN18.2 drugs in the treatment of gastric cancer. Sanyou was developing antibodies targeting CLDN18.2 at that time. "We were developing full-length antibodies and nanobodies at the same time, and the latter was making greater progress."
This antibody drug has obtained the implied approval for clinical trials from NMPA, and will be studied in the clinical trials for the treatment of CLDN18.2-positive advanced malignant gastrointestinal solid tumors.
In addition, Sanyou has accumulated experiences in the early discovery of dozens of other innovative antibody drugs and in the staged R&D of hundreds of projects. These experiences and advantages prepared Sanyou for more projects. "Now we have more than one hundred integrated projects and hundreds of staged projects under development."
Time for the innovative drugs R&D services to go abroad
According to Dr. Lang, Sanyou has provided services to or cooperated with more than 400 clients, where almost every existing client would seek cooperation for the second time, and some of them have worked with Sanyou on more than 10 projects. Sanyou will continue to expand its domestic and oversea business. "I hope to provide services for all pharmaceutical companies and biotech enterprises and boost their drug R&D." Dr. Lang says this is the core goal of Sanyou.
The business scope of Sanyou covers CRO, CPO (cooperative project organization), and CRS (core reagent solutions). CRO services range from target validation to PCC and to IND, and include monoclonal antibody, bispecific antibody, ADC, CAR-T and gene therapy; CPO services include PCC and IND directional R&D, cooperative R&D, and license transfer; and four categories of CRS core reagents include proteins, antibodies, cells and diagnostic reagents.
"I want to improve our one-stop services by integrating pre-clinical CDO on top of our existing services. A plant for the pilot production is under construction." said Dr. Lang, referring to Sanyou's strategic partnerships with Dragon Sail Pharmaceutical and other CDMOs to provide the integral pre-clinical solutions.
In terms of innovation, Sanyou is actively setting foot in various fields of the therapeutic technologies, such as PDC, trispecific antibodies, etc.
PDC refers to polypeptide coupling drugs. "We are planning to build a trillion-level polypeptide library for screening affinitive polypeptides, and hoping to make breakthroughs for intracellular targets." Dr. Lang proposes that peptides and micromolecular drugs may be coupled to enter the cell by taking advantage of the targeting ability of the peptides, and act on intracellular targets. "This is what we will focus on this year. At present, the preliminary research and design of the library have been completed, and the conceptual test is under way. It is expected to be launched in three months.
"At the same time, in the fields of tumors, autoimmune diseases, metabolic diseases, etc., scientists at Sanyou also help clients with target research and project validation through directional recommendation. He hopes to solve the problems with some highly challenging targets through these actions, so as to meet some unsatisfied demands for clinical disease treatment..
For example, G-protein-coupled receptors (GPCR), which play a significant role in diabetes, obesity, AD, and mental illness, have always been popular targets. A total of 475 micromolecular drugs targeting GPCR have been approved by the FDA, accounting for 35% of all FDA approved drugs. However, as they are tricky proteins with 7 transmembrane domains, instable target structure, complex conformation, low expression level, difficulty for protein preparation, and other characteristics, the development of biological drugs for GPCR is extremely challenging, and they are recognized as "ultra-difficult targets" in the industry.
"We have specialized teams working on these targets." According to Dr. Lang, the advantages of Sanyou's STAL discovery platform make it feasible for the complex screening of these highly challenging targets, and he also hopes to make breakthroughs in these areas.
In Sanyou, there are more than 10 innovative directions similar to GPCR, and every direction has its own team in charge. The discovery of more types of antibody drugs in the aid of vast antibody libraries, and the delivery of more projects for highly challenging targets are different innovative means aiming to provide more possibilities for the R&D of innovative antibody drugs, offer more solutions to meet clinical needs, make differentiated final products, and avoid unnecessary resource consumptions.
At present, five antibody drugs originated from Sanyou have been filed for or approved for the IND. "I hope the number will exceed 100 in the next decade," said Dr. Lang with great expectations.
Guojun Lang, Ph.D. of Zhejiang University and majored in Biochemistry and Molecular Biology, has specialized in the R&D and industrialization of innovative antibody drugs for more than a decade. In 2015, he led the foundation of Sanyou Biopharmaceuticals, and has served as the chairman and CEO. After 7 years of persistent endeavor, Sanyou has become an industry-leading company comprised with a team of more than 250 members and most of them have master's or doctoral degrees. Sanyou has provided innovative antibody drug R&D services to more than 300 pharmaceutical companies and drug R&D institutes around the world.
Before founding Sanyou, Dr. Lang worked as senior scientist, R&D manager, QC manager, product director and vice president of BD at Henlius (Shanghai) (an affiliate of Fosun Pharma), Henlius (USA) and Abmart. He was granted the 2013 Shanghai Science and Technology Innovation New Talent Award, the 2014 Shanghai Science and Technology Elite Candidate, and other honors.
Dr. Lang is experienced in the R&D, industrialization and commercial operation of antibody drugs. Among the drug R&D projects where he serves as a core member or the team leader, over 10 drugs have entered the stage of clinical trials, and several drugs have been launched onto the market, followed by dozens of other drugs in the pre-clinical R&D stages. The super-trillion antibody discovery platform developed by the team he leads boasts internationally leading core technical parameters. He once served as the leader or core R&D member of more than 10 major Provincial or National Major Scientific and Technol.