Li Li, who has been in Suzhou Laboratory for two years, can finally take a breath and go to his hometown in Hunan to spend a small holiday in the year of the tiger.
At this time two years ago, covid-19 epidemic began to rage. In the face of this new virus, the world was at a loss and had no medicine to solve. At that time, a search for covid-19 “specific drugs” kicked off among many scientific research teams at home and abroad. Li Li’s company Shanghai Junshi Biosciences Co.Ltd(688180) (688180. Sh, 01877. HK) has become the first enterprise to enter the clinical stage in the research and development of covid-19 neutralizing antibody in China.
Neutralizing antibody is an antibody with antiviral activity, which can recognize the virus surface protein. The difference from the vaccine is that the vaccine can induce spontaneous immunity, while neutralizing antibody can be directly used to block the infection of covid-19 virus to human cells. Neutralizing antibody drugs developed based on this mechanism have been proven to reduce viral levels in a variety of viral infections including HIV, Ebola, SARS and MERS, achieving a good target for antiviral therapy.
In the fight against covid-19 epidemic, neutralizing antibodies have high hopes, but the continuous variation of the virus and the risk of escape also challenge the efficacy of relevant drugs. In the past two years, Li Li and other R & D colleagues have been watching the “every move” of the virus.
“In the face of virus mutation, we will not choose to lie flat. We have a deeper understanding of the action mechanism of virus and antibody drugs. Compared with the initial investment in covid-19 neutralizing antibody research and development, our work has become more leisurely.” Li Li told the first financial reporter.
only used 4 months to enter the clinic
Li Li officially joined Shanghai Junshi Biosciences Co.Ltd(688180) in December 2019. What he didn’t expect is that he will lead the development of covid-19 neutralizing antibody as the project leader in two months. “On the first day of the Chinese New Year in 2020, media reports on covid-19 began to be overwhelming. At that time, we also received the urgent task of developing covid-19 drugs. Everyone gave up their vacation and hurried to the laboratory.”
Li Li said that his company chose neutralizing antibody as the incision for developing covid-19 drugs. Based on two considerations, one is that the company itself is an enterprise focusing on the research and development of biological macromolecular drugs. In terms of antibody research and development, from drug discovery, development and industrialization, it has established a mature full life cycle platform; The second is to establish long-term cooperation with the Partner Institute of Microbiology of the Chinese Academy of Sciences (hereinafter referred to as “Institute of Microbiology”) before the epidemic, and accumulate long-term cooperation foundation and trust. Over the years, the Institute of microbiology has used its own advantage platform to carry out the research and development of host receptors of various pathogens such as Zika and influenza virus and the screening of anti Mycoplasma antibodies in rehabilitated patients. Therefore, it is familiar with the role of neutralizing antibodies in the prevention and treatment of infectious diseases.
\u3000\u3000 “After the outbreak, the microbiological team and the company docked, and the two sides immediately started the covid-19 neutralizing antibody research. Using the mature single B-cell antibody screening platform, the Institute of Microbiology of the Chinese Academy of Sciences found the memory B cells that can recognize the S-protein RBD domain on the surface of covid-19 virus from the sera of rehabilitated patients, and screened several candidate antibodies, which will be ready in early February 2020 Select the antibody sequence and hand it over to the company. In the process of cooperation, the company not only undertakes the transformation of this project, but also works with the Institute of microbiology to study how the antibody can be made into medicine and how to make the antibody have better antiviral activity. ” Li Li said.
After obtaining multiple candidate antibody sequences, challenges ensue, because a conventional antibody drug often takes 18 months from development to clinical application, but in a special period such as the epidemic, the time can not afford, and the development process must be accelerated.
“Looking at China’s biopharmaceutical industry, it only flourished around 2015 and is still in the process of absorbing foreign advanced experience. In the face of sudden new viruses, it is impossible to copy the operation of drug development. We choose to take the initiative to take risks and try boldly. We can feel the stone to cross the river all the way down.” Li Li said.
In order to quickly promote neutralizing antibodies to the clinic, Shanghai Junshi Biosciences Co.Ltd(688180) chose the “combination fist” method, which not only developed multiple antibodies synchronously, but also adopted at least three schemes at the same time in the protein acquisition stage. Finally, it was determined to use instantaneous transfection samples for preclinical research, The non monoclonal stable cell pool samples were used for pharmacological toxicology and early clinical sample process development, and the industrialization scheme of monoclonal stable transfected cell lines for clinical trials was constructed simultaneously.
Li Li said that generally speaking, in order to commercialize long-term drug supply, pharmaceutical enterprises will adopt the monoclonal stable transfection cell line mode in large-scale production, which has the advantages of safety, stability and large-scale effect. However, it usually takes 4-6 months to build a stable transfection cell line. Obviously, the epidemic situation does not wait. In order to make up for this time difference, The first mock exam was launched to construct a cell line and to start a transient program to meet the needs of pre clinical evaluation and process development such as animal experiments. This model can get protein in a short time, but the capital investment is also huge.
After four months of hard work, Shanghai Junshi Biosciences Co.Ltd(688180) has completed protein expression and engineering transformation. Through in vitro and in vivo experiments, it is finally determined that js016 antibody (etecivir monoclonal antibody) has become a clinical candidate. The antibody neutralization test of vid-js016 was the first clinical trial of vid-js19 in Huashan University Hospital in the world, and it was the first time that the antibody neutralization test of vid-js016 was completed in the 19th month of June 2020, Overseas clinical trials of js016 were also launched simultaneously.
Li Li’s home is in Shanghai. In the first half of 2020, together with many colleagues, he took root in the company’s Suzhou laboratory and almost regarded the company as a family. “Everyone worked overtime and was racing against the epidemic in order to speed up the progress of drug research and development and promote the drug into clinical practice as soon as possible. At that time point, everyone was under great pressure and their nerves were highly strained.”
epidemic situation keeps , R & D work keeps
In May 2020, Shanghai Junshi Biosciences Co.Ltd(688180) awarded the overseas clinical development and commercialization of js016 to Lilly, a multinational pharmaceutical company. Since February 2021, the double antibody therapy composed of this antibody and another neutralizing antibody drug of Lilly, “bancivir monoclonal antibody”, has been authorized for emergency use in more than 15 countries and regions around the world, including the United States and Italy. Among them, in the United States, it has been authorized for covid-19 treatment and post exposure prevention of specific populations, It is the first and only neutralizing antibody therapy authorized for treatment and prevention in people under the age of 12.
In the fight against covid-19 epidemic, covid-19 neutralizing antibody as a preventive and therapeutic drug has played a positive role, but it is not impeccable. For example, the variation of virus may lead to drug failure.
The Omicron mutant, which first appeared in South Africa in November 2021, is now replacing Delta and has become popular all over the world. There are more than 30 variations on the surface spike protein of the mutant. Covid-19 virus infects the human body through the combination of spike protein and human cell receptor, and spike protein is also the binding target of many neutralizing antibodies.
When the Omicron mutant began to appear, it once triggered a global panic and caused a “bloody storm” in the capital market. For example, at the end of November 2021, the stock prices of many covid-19 neutralizing antibody enterprises around the world fell sharply.
Omicron mutant is now gradually impacting the listed covid-19 neutralizing antibody drugs. The FDA announced that the use of these antibodies was limited to the local monoclonal antibody 8180 {016} in 2022.
\u3000\u3000 “We have expectations for virus mutation. When we applied for js016 project, we considered cocktail therapy. There are multiple antibody candidates that can form combination therapy with js016. We don’t think the sky will fall because of virus mutation, nor will we choose to lie flat. Instead, we think about how to improve the drug and upgrade it from version 1.0 to version 2.0. Over the past two years, we have Continued to study the mechanism of action of antibody drugs and accumulated rich experience in the field of antiviral. ” Li Li said.
In 2021, Li Li invested in the development of another covid-19 neutralizing antibody js026 injection, which has the potential of combined use with js016, and was approved for clinical trial 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 research of new mutated viruses and new antibodies. At the same time, another R & D team of Shanghai Junshi Biosciences Co.Ltd(688180) is vigorously promoting the clinical research of anti covid-19 virus small molecule drugs.
Li Li said that in the fight against covid-19, neutralizing antibodies have proved their value and have the potential to become “the hope of the people”. However, due to the characteristics of antibody drugs, the production cost is high and the portability of transportation and use is limited. Therefore, it is difficult to achieve a wide range of coverage for developing countries and low-income people. If neutralizing antibodies are to become universal drugs, the integration of production capacity from all parties and the support of governments are essential.
Whether covid-19 oral small molecule drugs will replace covid-19 neutralizing antibodies has also aroused discussion. In Li Li’s opinion, even with small molecule drugs, neutralizing antibodies will not be replaced. The richer the means to treat covid-19, the better. “Any kind of drug may face the problem of drug resistance escape. When the vaccine immune barrier is erected, various therapies such as neutralizing antibodies and small molecule drugs can help humans face covid-19 virus more calmly.”
Li Li said that if the epidemic continues, their R & D work will not stop. When the epidemic began to appear, many companies invested in relevant drug R & D, some of which have been temporarily shelved, but they are still holding on and preparing to hold on to the end. Since coronavirus has entered human society, it will not leave easily. Maybe after ten or twenty years, pandemic will still appear. What they are doing now is not only to solve the current problems, but also to prepare for the fight against related viruses in the future.
