Recently, the Institute of Infectious Diseases (IHU) of the Mediterranean University Hospital in Marseille, France, reported that the new strain of the new coronavirus variant B.1.640.2 carries 46 mutations. Nearly 2 months ago, the southern African country of Botswana detected the new coronavirus variant B.1.1.529 for the first time in a confirmed case, which was subsequently named Omicron by the World Health Organization (WHO), posing a huge challenge to existing vaccines and antiviral therapies around the world.
In this uncertain battle against the epidemic, "scientific tools" continue to race against time. "From the early days of the outbreak to the present, our team has not stopped studying and evaluating new mutant strains." Recently, Professor Zhang Linqi of Tsinghua University School of Medicine and Vanke School of Public Health and Health told the surging news (www.thepaper.cn) reporter that in the past 2 years, its team has screened thousands of antibodies against the new crown virus, and each time a mutant strain appears, they can conduct a comprehensive assessment, and also have a very comprehensive "antibody reserve".
Previously, on the evening of December 8, 2021, the anti-coronavirus antibody combination drug ambavir monoclonal antibody combination drug ampavirus/romidavir monoclonal antibody combination drug jointly developed by the team of Professor Zhang Linqi, the team of Professor Wang Xinquan of the School of Life Sciences of Tsinghua University, the team of Professor Zhang Zheng of the Third People's Hospital of Shenzhen, and the combination of anti-coronavirus antibodies (formerly known as BRII-196/BRII-198 combination therapy) was jointly developed by Tengsheng Bo Pharmaceutical, Tsinghua University and the Third People's Hospital of Shenzhen. It was officially approved for listing by the China Food and Drug Administration, becoming the first self-developed anti-new coronavirus antibody drug in China.
Professor Zhang Linqi's team. Tsinghua University Figure
Combination ambavirumab/romimab is used to treat adults and adolescents (12-17 years, weighing ≥40 kg) with mild and ordinary types who are associated with high-risk factors for progression to severe (including hospitalization or death) with novel coronavirus infection (COVID-19). Among them, adolescents (12-17 years old, body weight ≥40 kg) are conditionally approved. Its approval is based on a Phase 3 clinical trial of ACTIV-2 supported by the National Institutes of Health (NIH), which included positive interim and final outcomes in 847 enrolled patients. The final results showed that the combination of amphavir monoclonal/romizumab reduced the risk of hospitalization and death in COVID-19 outpatients at high risk of clinical progression by 80% (78% in the medium term) compared with placebo, which was statistically significant.
As of its approval for marketing, laboratory development and clinical trials of this antibody combination drug took 20 months. "Whether it's antibodies or small molecule drugs, in response to the widespread epidemic, we hope that more drugs will be on the market, and any drug has its unique value." Luo Yongqing, CEO of Tengsheng Huachuang, told the surging news (www.thepaper.cn) reporter that for several neutralizing antibodies and small molecule drugs that have been approved for marketing around the world, "it is not a completely competitive situation, in some cases it is a complementary relationship, and the two types of drugs have different use scenarios and approaches." ”
Mutations in "nature" and persistent challenges
After Alpha, Beta, Gamma and Delta, Omi kerong is the fifth new coronavirus variant of global concern who has been included. For the latest IHU variant, WHO epidemiologist Abdi Mahamud also said at a press conference in Geneva on 4 January, "The variant is already within our focus." ”
In fact, Omi kerong has just set off a wave of new research and testing in the global scientific community. The latest WHO Weekly REPORT on covid-19 epidemics shows that the overall risk associated with the Omilkejunn variant remains high for the week ended 26 December 2021. Consistent evidence suggests that the Opmikharon has a reproductive advantage over the Delta variant, with a doubling time of 2-3 days.
As of the time of the weekly report, incidence had increased rapidly in many countries, including those where the strain had become dominant, such as the United Kingdom and the United States. However, a decrease in incidence has been observed in South Africa. Early data from the UNITED Kingdom, South Africa and Denmark suggest that the risk of hospitalization is lower than that of the Delta variant, however, further data are needed to understand clinically serious markers including oxygen use, mechanical ventilation, and death. The effect of vaccination and pre-existing infections on post-infected severity also requires further study.
After the attention of Omilon, its impact on vaccines and existing antibodies and small molecule drugs is also worrying, and similar tests have actually been repeated many times in the past 2 years. Zhang Linqi previously said in an interview with the surging news reporter that as one of the RNA (ribonucleic acid) viruses, people do not need to be surprised by the mutation of the new crown virus, "Its own replication machine in the replication process is not as accurate as human gene replication, which is a kind of 'nature' of RNA viruses." ”
Earlier, when the alpha variant (B.1.1.7) spread, Zhang Linqi's team also quickly completed the assessment. In an interview with The Paper in January last year, he said, "From the current situation, B.1.1.7 will not have a negative impact on the antibody drugs and vaccines we are studying, so we can breathe a sigh of relief for the time being." ”
For the arrival of the Aomi Keron, the research team also reacted quickly. Luo Yongqing mentioned that the Tengsheng Huachuang team had already begun experiments on the Aomi Kerong variant a few weeks ago. According to the company's official data, although the activity of ampavirub against the Omilcroon variant strain decreased significantly, the romexvir maclizumab was not affected by the Omilcroon variant strain. Ultimately, the combination of ambavirumab/romizumab maintained neutral activity against the Omikejong variant strain.
China's first self-developed anti-new coronavirus antibody drug ampavirinumab / romidavir monoclonal antibody combination therapy.
This is one of the few antibody therapies in the world that still maintains good neutralization activity against the Omikejong strain. This result has also been verified by other laboratories internationally. On December 23, 2021, Nature, a top international academic journal, simultaneously published five papers online evaluating the effectiveness of vaccines and antibodies against the Omiljung strain of the new coronavirus. He Dayi, a professor at Columbia University School of Medicine, and colleagues mentioned in one of their papers that COVID-19 vaccines and therapies have a much worse effect on Omiljung.
The research team investigated the neutralizing activity of four major COVID-19 vaccines — Pfizer-BioNTech, Modena, Johnson & Johnson, and AstraZeneca — in samples from 54 participants, all of whom received two full doses of the vaccine (15 of whom were also given boosters from Pfizer-Biotech and Modena). A significant decline in anti-Omilon effectiveness has been observed in all vaccine types, including two participants who have been infected with COVID-19. However, in samples of participants who were vaccinated with Pfizer-Biotechnology or Modena booster needles, their antibody neutralization rates decreased less.
He et al. also studied the neutralizing activity of 19 monoclonal antibodies against the Omikejong variant spike protein. The monoclonal antibodies tested included clinically approved therapeutic antibodies such as REGN10987 (imdevimab), REGN10933 (casirivimab), COV2-2196 (tixagevimab), COV2-2130 (cilgavimab), LY-CoV555 (bamlanivimab), CB6 (etesevimab), Brii-196 ( amubarvimab), Brii-198 (romlusevimab) and S309 (sotrovimab). The results showed that 17 of the 19 monoclonal antibodies lost complete or partial neutralization capacity. Only romlusevimab and sotrovaimab retained neutralization activity. romlusevimab is the romexpressumab provided by Tengsheng Huachuang.
It is worth noting that the reason why the mutation on the spike protein (S protein) of the new coronavirus is that it plays a key role in entering human cells, and the spike protein can bind to the ACE2 receptor of human cells, which is also the main target of vaccine and drug therapy design and manufacturing.
Dr. Zhu Qing, senior vice president of Tengsheng Bo Pharmaceutical and head of the biopharmaceutical department, introduced, "The place where the new crown virus and ACE2 combine is also the site of most antibody recognition, and Delta mutations in this area are still very few, while the number of mutations in Omi Kerong in this area has increased greatly. "It is precisely because of these changes that most of the antibodies have lost a lot of activity against the Omicron variant."
How are antibodies designed? How to deal with the next mutation
Who wins, the speed of drug development and marketing and viral mutations? Even if it works for now, will the next sudden attack still be able to withstand it? Scientists around the world have no way of giving definitive answers to these questions.
The antibody evaluation work of Zhang Linqi et al. made a breakthrough on March 5, 2020, when the team first identified the highly effective new crown neutralizing antibody P2C-1F11 (later named BRII-196), which was also one of the key antibodies in the later antibody combination therapy specific drugs. On March 30, 2020, Nature published one of the mechanistic research results of Zhang Linqi et al. online, "The Structure of the Binding Domain of the New Coronavirus Spike Protein Receptor and the Receptor ACE2 Complex". Subsequently, the research team published an article in Nature, entitled "Isolating highly effective neutralizing antibodies from the body of new crown infected people".
The drug development idea of antibody combination therapy amphavir monoclonal antibody/romizumab was determined on April 11, 2020. Zhu Qing talked about the original intention of starting to develop this pair of antibody combination therapy, "From the outbreak of the epidemic, when the design of this pair of antibodies began, it was considered that the virus is a very new RNA respiratory virus, according to experience, the mutation rate of the virus is very high, so in the unknown situation, the team specially designed this antibody to use combination therapy, including deciding that the antibody will target different binding sites." ”
The new coronavirus mainly infects human cells by binding to ACE2 on human cells and causes disease through cell reproduction. "Amphavir monoclonal antibody blocks the virus from binding to ACE2 at the site where the new coronavirus receptor binding region directly binds to ACE2, while romizumab blocks the reproduction of the virus with different mechanisms of action for another site in the new coronavirus receptor binding region that does not bind to ACE2."
Zhu Qing also mentioned, "In terms of dose selection, many companies have approved doses that are 2-4 times lower than Tengsheng Huachuang, and when they are less active against new mutant strains, these doses are unlikely to obtain good therapeutic effects." Ambavir monoclonal antibody/romimab combination therapy is a single intravenous dose in which intravenous blood antibody concentrations rise very quickly, and with our dose selection, blood antibody concentrations of 300-400 mg per milliliter can be quickly reached within a few hours. She added that this data shows that at such high concentrations, the highest antibody concentrations of ampavivir monoclonal antibody/romizumab in human serum can reach thousands of times the IC50 value and 100 times the IC90 value against the Omikejong mutant strain.
In addition, the research team designed the antibody to extend the half-life of the antibody. "In general, the serum half-life of a person is 3-4 months, and by technically modifying the Fc part of the antibody, the antibody can be extended to 2-4 times, so this can also ensure that within a few weeks of administration, the antibody can maintain a high blood concentration and strengthen the ability to neutralize activity."
Luo Yongqing told the surging news reporter that compared with small molecule drugs, neutralizing antibodies have several different characteristics. "First of all, the mechanism of action of macromolecular neutralizing antibodies is not the same as that of small molecule drugs, macromolecular neutralizing antibodies take effect immediately through intravenous infusion, which is better for viruses that replicate very quickly, and from this level, neutralizing antibodies have an advantage, quickly reaching the highest blood concentration through intravenous injection to neutralize the virus." In addition, we selected two of the strongest antibodies from hundreds of antibodies, and they are elite antibodies with complementary effects, and we copy them thousands of times for human treatment, which can play a very good therapeutic effect in the short term. In addition, antibodies have an immunomodulatory effect, and the immunity time of this drug is formed is 9-12 months. Overseas, antibody drugs are approved as indications for COVID-19 prevention and can be complementary to vaccines.
He believes that, taken together, neutralizing antibodies are drugs that are managed from preventing infection to blocking mild infection to severe infection and death. Of course, Luo Yongqing also mentioned that small molecule drugs are an enzyme that inhibits viral replication or reduces the load of viral replication by inhibiting key steps in the replication process, and the advantage is that it is convenient to take orally and low cost.
Luo Yongqing stressed, "The two types of drugs are not a completely competitive situation, in some cases are complementary, the two types of drugs have different use scenarios and ways, we expect more drugs to be approved for marketing to control the development of the new crown epidemic." ”
Zhang Linqi also told the surging news reporter that antibodies are natural killing weapons produced by the human body itself, and have accurate targeting of viruses, so they are not inferior to other types of antiviral drugs in terms of antivirals. At the same time, because antibodies are natural biological weapons and an important part of human immunity, they can quickly improve the body's own immunity while playing an antiviral role, helping the human body build an immune barrier, which has two effects.
It is worth noting that when the antibody therapy was approved for marketing in China, Zhang Linqi said that the next step will continue to study the preventive effect of monoclonal antibody combination therapy in high-risk and immunodeficiency populations. He said at the data sharing meeting on the same day that regarding the role of this antibody in prevention, clinical research is being carried out by Academician Zhong Nanshan with the support of the Ministry of Science and Technology, especially some related studies for immunodeficient patients.
Zhang Linqi told the surging news reporter that in the past 2 years, through cooperation with Tengsheng Bo Pharmaceutical and Shenzhen Third People's Hospital, its research team has obtained thousands of antibodies, and with the joint efforts of relevant cooperative teams, there has been great research and development progress, "also look forward to the future, we not only through the expansion of indications to show our research and development capabilities, we also want to get more information on disease escape, so that in more scenarios, more people to give full play to the role of drugs." ”
He said that studying viral mutations is one of the most important directions for his team, including the new crown virus, HIV, etc., "The goal of the research is to find broad-spectrum neutralizing antibodies." Zhang Linqi said that the specific work carried out by the laboratory is to evaluate the thousands of antibodies found in an all-round way, and the preliminary results show that some very good antibodies with broad-spectrum neutralization ability have indeed been found.
When these antibodies are commercially developed, clinical trials and follow-up promotion work is decided according to the actual development of the epidemic and the changes in the epidemic situation. "But there is no doubt that from the field of basic research, we have obtained very good 'seeds' through selection, providing important technical materials for our future research and development and industrialization development."