Li Li, who has been guarding the Suzhou laboratory for two years, can finally take a breather and go to his hometown in Hunan to spend a small holiday during the Spring Festival of the Year of the Tiger.
At this time two years ago, the new crown epidemic began to rage, in the face of this new virus, the world is helpless, there is no cure, at that time, a search for a new crown "special drug", in many scientific research teams at home and abroad. Li Li's company Junshi Bio (688180. SH and 01877.HK), which became the earliest enterprises in the domestic research and development of new crown neutralizing antibodies to enter the clinical stage.
Neutralizing antibodies are antibodies with antiviral activity that can recognize viral surface proteins, unlike vaccines in that vaccines induce spontaneous immunity in the body, while neutralizing antibodies can be used directly to block the infection of human cells by the new crown virus. Neutralizing antibody drugs developed based on this mechanism of action have been shown to reduce viral levels in a variety of viral infection diseases, including HIV, Ebola, SARS, MERS, etc., and achieve a good targeted antiviral therapy effect.
In the fight against the new crown epidemic, neutralizing antibodies have been placed high hopes, but the continuous mutation of the virus, the risk of escape, but also to challenge the efficacy of related drugs, in the past two years, Li Li and other research and development colleagues, has been closely watching the virus 'every move].
"In the face of viral mutations, we will not choose to lie flat, we have a deeper understanding of the virus, the mechanism of action of antibody drugs, compared to the initial investment in the development of new crown neutralizing antibodies, now our work is more relaxed." Li Li told the first financial reporter.
It took only 4 months for the drug to enter the clinic
Li Li officially joined Junshi Bio in December 2019, and what he did not expect was that two months later, he would lead the development of the new crown neutralizing antibody as the project leader. "On the first day of the Chinese New Year in 2020, the media coverage of the new crown began to overwhelm, and it was at that time that we received the urgent task of developing the new crown drug, and everyone gave up their vacation and rushed to the laboratory."
Li Li said that his company chose neutralizing antibodies as an incision for the development of new crown drugs, based on two major considerations, one is that the company itself is an enterprise with the research and development of biological macromolecules as the core, in terms of antibody research and development, from drug discovery, to development, to industrialization, has established a mature life cycle platform; the second is that it has established long-term cooperation with its partner The Institute of Microbiology of the Chinese Academy of Sciences (hereinafter referred to as the "Institute of Microbiology") has established long-term cooperation before the epidemic and accumulated a long-term cooperation foundation and trust. Over the years, the Institute of Microbiology has used its own advantageous platform to carry out research and development work on the screening of various pathogen host receptors such as Zika and influenza viruses and anti-pathogen antibody screening for rehabilitation patients, so it is familiar with the role of neutralizing antibodies in the prevention and treatment of infectious diseases.
"After the emergence of the epidemic, the microbial team and the company docked, the two sides hit it off, began the new crown neutralization antibody research, the Institute of Microbiology of the Chinese Academy of Sciences used a mature single-cell antibody screening platform, from the serum of recovered patients to find memory B cells that can recognize the S protein RBD domain on the surface of the new crown virus and screened to several candidate antibodies, in early February 2020, the candidate antibody sequence was handed over to the company, in the process of cooperation, the company is not only undertaking the transformation of this project, At a very early age, we worked with the Institute of Microbiology to study what kind of antibodies can be drugged and how to make the antibodies have better antiviral activity. Li Li said.
After obtaining multiple candidate antibody sequences, challenges follow, because a conventional antibody drug, from development to clinical, often takes 18 months, but in special periods such as the epidemic, time is simply not consumed, and the development process must be accelerated.
"Looking at the domestic biopharmaceutical industry, it is also booming and growing around 2015, and it is still in the process of absorbing advanced foreign experience." In the face of the sudden new virus, drug development is impossible to copy the operation, we choose to take the initiative to take the risk, boldly try, all the way down, it can be said that it is a stone crossing the river. Li Li said.
In order to quickly promote the neutralizing antibody to the clinic, Junshi Bio chose the "combination fist" approach, not only for the synchronous development of multiple antibodies, but also took at least 3 schemes at the same time in the protein acquisition stage, and finally determined the use of transient transfection samples to carry out preclinical research, the use of non-monoclonal stable cell pool samples for pharmacology and toxicology and early clinical sample process development research, and the synchronous construction of monoclonal stable transfected cell lines for clinical trials.
Li Li said that in general, in order to commercialize long-term drug supply, pharmaceutical companies will use monoclonal stable transfection cell line mode in large-scale production, which has the advantages of safety, stability and scale effect, but it usually takes 4-6 months to build a stable cell line, obviously the epidemic situation does not wait for people, in order to make up for this time difference, the company chose to start the instantaneous program at the same time as building the cell line to meet the sample needs of animal experiments and other preclinical evaluation and process development, this model can obtain protein in a short period of time. But the investment is also huge, and the company has no cost in this project.
After four months of hard work, Junshi Bio completed the protein expression, engineering transformation, and finally determined that JS016 antibody (ettexvirumab) became a clinical candidate through in vitro and in vitro experiments. On June 7, 2020, JS016 completed the first subject administration of the Phase I clinical trial in Huashan Hospital affiliated to Fudan University, and completed the enrollment of subjects in early July, which is the world's first clinical trial of new coronavirus neutralizing antibodies in healthy subjects, JS016 is also the earliest neutralizing antibody to the new coronavirus in the clinical stage in China, and the overseas clinical trials of JS016 have also been launched simultaneously.
Li Li's home is in Shanghai, and in the first half of 2020, he and many colleagues took root in the company's Suzhou laboratory and almost regarded the company as home. "Everyone is working overtime, racing against the epidemic, in order to speed up the progress of drug research and development, as soon as possible to promote drugs to the clinic, at that point in time, everyone's pressure is very large, the nerves are in a highly tense state."
The epidemic is not stopping, and the research and development work is not stopping
In May 2020, Junshi Bio awarded JS016 overseas clinical development and commercialization to Eli Lilly, a multinational pharmaceutical company. Since February 2021, the dual antibody therapy composed of this antibody and another neutralizing antibody drug of Eli Lilly, "Barnivumab", has been authorized for emergency use in more than 15 countries and regions around the world, including the United States and Italy, of which the United States has been authorized for COVID-19 treatment and post-exposure prevention in specific populations, and is the first and only neutralizing antibody therapy authorized for treatment and prevention in people under 12 years of age.
In the fight against the new crown epidemic, the new crown neutralizing antibodies as preventive and therapeutic drugs have played a positive role, but they are not invulnerable, such as the mutation of the virus, which may cause the drug to fail.
The Semicon variant, which first appeared in South Africa in November 2021, is now replacing Delta and is becoming popular around the world, with more than 30 mutations on the surface spike protein of the mutant strain, and the new crown virus infects the human body through the binding of spike protein to human cell receptors, and spike protein is also the binding target of many neutralizing antibodies.
When the Omicron variant began to appear, it once caused global panic and caused a "bloody storm" in the capital market, such as at the end of November 2021, the stock prices of many new crown neutralizing antibody companies around the world fell sharply.
The Omiljunn variant is now gradually neutralizing antibody drugs in impact on the market. On January 24, 2022 local time, the US FDA announced that the emergency use authorization of two new crown dual antibody therapies will be modified to limit the use of only mutant strains that are sensitive to these neutralizing antibodies, including Junshi Bio's JS016 and Eli Lai's barnivumab double antibody therapy.
"We had expectations for viral variants, and when we first applied for the JS016 project, we took into account cocktail therapy, and there were multiple antibody candidates that could be combined with JS016. We don't think the sky is falling because the virus mutation occurs, nor do we choose to lie flat, but think about how to improve the drug, upgrading from version 1.0 to version 2.0. For two years, we have continued to study the mechanism of action of antibody drugs and accumulated rich experience in the field of antivirals. Li Li said.
In 2021, Li Li invested in the development of another new crown neutralizing antibody, JS026 injection, which has the potential of combined drug use with JS016, and was approved for clinical trials in China in November of the same year. After the drug was sent to the clinic, Li Li's antibody research and development team re-invested in the study of new mutant viruses and new antibodies. At the same time, another R&D team of Junshi Bio is intensively promoting the clinical research of anti-new coronavirus small molecule drugs.
Li Li said that in the fight against the new crown, neutralizing antibodies have proved their value and have the potential to become the "hope of the people", but also due to the characteristics of the antibody drugs themselves, the production costs are high, and the portability of transportation and use is limited to a certain extent, so it is difficult to achieve large-scale coverage of developing countries and low- and middle-income people. If neutralizing antibodies are to become universal medicines, the integration of production capacities from all parties and the support of governments are indispensable.
Whether the new crown oral small molecule drugs will replace the new crown neutralizing antibodies has also triggered discussions. In Li Li's view, even with small molecule drugs, neutralizing antibodies will not be replaced, and the more abundant the means of treatment of new crown, the better. "Any drug could face a drug-resistant escape problem. When the vaccine immunity barrier is erected, various therapies such as neutralizing antibodies and small molecule drugs can help human beings face the new crown virus more calmly. ”
Li Li said that the epidemic does not stop, their research and development work will not stop, when the epidemic began to appear, many companies are invested in the development of related drugs, some have been temporarily shelved, but they are still insisting, ready to persist to the end. Since the coronavirus has entered human society, it will not leave easily, and it may be ten or twenty years later that the pandemic will still appear. What they are doing now is not only to solve the current problems, but also to prepare for the future fight against the relevant virus.