Neutralizing antibodies:

The hope and unknown of the new crown special medicine

  Reporter of China News Weekly/Peng Danni

  Issued in the 954th issue of China News Weekly, 2020.7.06

  On June 15, "Science" magazine published 5 articles related to neutralizing antibodies in one breath. Several teams from the Netherlands and the United States reported on the different neutralizing antibodies they screened. On June 22nd, Chen Wei of the Academy of Military Medical Sciences of the Academy of Military Sciences and Zhou Qiang of West Lake University and others also published the monoclonal neutralizing antibodies they found in the journal...Research progress on neutralizing antibodies has continuously emerged in academic journals, Let people feel deeply in the new crown epidemic situation, this seems to be a new life-saving straw.

  The receptor binding domain on the spike protein S protein on the surface of the new coronavirus is like a paw. By grabbing a receptor called ACE2 on the surface of human cells, it can enter human cells and achieve a large amount of virus replication. Antibodies that recognize and bind to specific "paws" on the surface of the virus and preemptively prevent the virus from binding to human cells are called neutralizing antibodies.

  The principle of the vaccine is to allow the body's immune system to recognize the virus and activate antibodies that have a strong neutralizing ability to the virus, and antibody drugs are more direct-scientists pass a series of tests in the laboratory to screen out the neutralization The most active antibody directly achieves treatment and prevention. Right now, part of the neutralizing antibodies in the world has begun a human trial, and its research heat and progress are second only to the vaccines that have been widely watched.

"The next'big event' of the new crown epidemic"

  Pete Hotts, a vaccine scientist at Baylor University School of Medicine, believes that monoclonal antibody therapy has great potential to become the next "big event" in the new crown epidemic. The so-called monoclonal antibody is simply to choose one antibody, corresponding to the "cocktail therapy" of a combination of multiple antibodies.

  In April of this year, 12 top scientists, including Nobel Prize winner in Physiology or Medicine, submitted to the US government a copy of the “Manhattan Plan for the New Crown Age”, stating that the second wave of new coronary pneumonia should be prevented , Monoclonal antibodies are the most promising antiviral option.

  Taking blood in the recovered new crown infection, choosing the most effective antibody, replicating it and making it into medicine-this can be seen as a "modern version" of recovery plasma therapy. This therapy is a traditional passive immunotherapy method by collecting the antibody-rich blood of patients in the rehabilitation period and infusion to other patients after treatment.

  As early as February this year, during the Wuhan Anti-epidemic Period, there were trials to collect plasma from patients in the rehabilitation period for this therapy. But this method cannot be pushed out on a large scale because of many restrictions. Ding Sheng, Dean of the School of Pharmacy, Tsinghua University, explained to China News Weekly that the main reason is that the source of therapeutic plasma is limited, the antibodies in different people are not the same, and the active concentration is also different, so the therapeutic effect will change . The long-term and more useful research and development strategy is to find, isolate, and identify these different neutralizing antibodies from patients in rehabilitation period, and finally select specific antibodies for subsequent development based on the function, that is, to develop antibody drugs.

  Ding Sheng explained that the neutralizing antibody is mainly through single cell sequencing of the patient's B lymphocytes, using different parts of the new coronavirus S protein as an antigen to interact with the cell, and then looking for a high affinity neutralizing antibody, and then through some engineering Means to adjust, optimize and clone antibodies to complete the screening and large-scale production of neutralizing antibodies.

  On May 4, researchers from the University of Utrecht and Erasmus Medical Center in the Netherlands reported in the journal Nature-Communication that they had identified an effective antibody from the human body. Subsequently, institutions including Harvard University and Rockefeller University also reported their neutralizing antibodies. On May 26, "Nature" magazine published the results of antibody research by Tsinghua University School of Medicine Zhang Linqi, Tsinghua University School of Life Wang Xinquan and Shenzhen Third Hospital Zhang Zheng and others.

  On the same day, Yan Jinghua and Gao Fu from the Institute of Microbiology of the Chinese Academy of Sciences; Yuan Zhiming from the Wuhan Institute of Virology; Wang Fusheng from the National Center for Disease Control and other researchers’ neutralizing antibody research results were also published online in Nature, the first in the world to advance to the Ganges A neutralizing antibody for monkey experiments. This neutralizing antibody was named "JS016", and later phases of clinical trials and commercialization were promoted by Junshi Biology, and its Phase I clinical trial was co-chaired by Professor Zhang Jing and Zhang Wenhong of Huashan Hospital.

  On June 1, the American pharmaceutical company Eli Lilly announced that a neutralizing antibody developed in cooperation with AbCellera of Canada has entered Phase I clinical trials and is currently undergoing the first batch of clinical trials in 32 inpatients with new crowns in the United States.

  Abroad, in addition to the AbCellera and Eli Lilly antibodies, the two antibodies jointly developed by Vir Biotechnology and GlaxoSmithKline, and the neutralizing antibody developed by American Regeneration Corporation are expected to enter the clinical development stage this summer. In China, Tengshengbo Pharmaceutical has reached a cooperation with the research teams of Tsinghua University and Shenzhen Third Hospital to jointly develop a variety of monoclonal neutralizing antibodies; companies such as BeiGene, Heplatin Pharmaceutical, and Ai Yue are all participants in R&D.

  The R&D schedule of the New Crown Neutralizing Antibody is being significantly reduced. Ding Sheng said that it usually takes a year or two to develop a new antibody drug and then enter clinical trials, but now the process is completed in three or four months. Lan Fei, a professor from Fudan University's Biomedical Research Institute, also participated in this antibody R&D competition. He told "China News Weekly" that they started research in February this year. At the end of March, they had screened more than 700 antibodies from more than 1,000 B cells, and finally got 11 candidate neutralizing antibodies. These neutralizing antibodies range from small-scale and medium-scale tests, to large-scale cultivation, large-scale purification, and then to clinical trials. The more stable timetable is around October this year.

  Lan Fei was mainly engaged in the basic science of antibody research, and had not done any clinical application research. However, he said that the research and development process of such drugs is actually more engineering-oriented, and the scientific challenges are not big. The general ideas and practices of neutralizing antibody research and development are similar, and each research and development team competes for resources. Although it only took more than a month to find antibodies, their neutralizing antibodies are now waiting in line for monkey testing, because there are only three or four P3 laboratories in China that can carry out monkey tests for new coronavirus.

A costly temporary passive immunity

  In fact, the development of antibody drugs in the field of antivirals has been slow before, and only two drugs have been launched globally. In the epidemic of sudden infectious diseases, neutralizing antibody drugs have never been really used.

  In response to the Middle East Respiratory Syndrome MERS, the m336 antibody jointly developed by the Futian University School of Basic Medicine Ying Tianlei and the National Institutes of Health in 2015 can be seen to be very effective in marmoset and rabbit animal models, but Failure to continue to advance to clinical.

  "This is a more conventional drug. It has also been researched and developed on other viruses. It is a proven path, but whether it is ultimately effective or safe enough requires further verification in the human body." Ding Sheng believes that it can only be said that the possibility is relatively high, but whether it will definitely pass is actually unknown.

  Jin Dongyan, a virologist and professor at the School of Biomedical Sciences of the University of Hong Kong, told China News Weekly that vaccines are actively immunized, while antibody drugs are called passive immunizations. It actually mimics human immune responses, but only one of them . Visually speaking, it is to find a unit in the Human Immunization Corps, clone a lot of it, and then defeat the virus, but it has lost many parts of the immune response.

  The timing of use is also important. Jin Dongyan explained that antibody drugs are not magic drugs. If the virus replication in infected people is already high, neutralizing antibodies will be difficult to fight. On June 3, the results of a clinical trial of 103 patients published in the Journal of the American Medical Association showed that in patients with severe and critical recurrent coronary pneumonia, plasma therapy was added to the recovery period on the basis of standard treatment, and the clinical improvement index was 28 days. There is no statistical difference.

  Ding Sheng explained that vaccines are used for prevention and antibody drugs are mainly used for treatment. The half-life of antibody drugs may be only a few weeks. Although it takes longer than those of small-molecule drugs taken orally, it is still a short-term immunity compared to vaccines. However, if you do not count the cost, healthy people can also use antibody drugs to protect.

  But cost is not a problem. Lan Fei said that the currently listed antibody drugs are mainly used in cancer treatment, and the price of a tumor antibody drug is between 50,000 and 100,000 yuan. The cost of a new coronavirus neutralizing antibody is about 1,000 yuan. According to the regulations, the price of antibody drugs is usually about 5 times the cost. If the effect is better, the effect of an antibody can last for about a month, which is cheaper than tumor antibody drugs, but it is still higher than traditional small molecule drugs taken orally.

  Eli Lilly's chief scientific officer Daniel Skovronsky said in an interview with the media that the global antibody production capacity cannot provide sufficient doses for billions of people to preventive use of neutralizing antibodies, so a better solution is to wait until the vaccine is available Extensive vaccination for the population, leaving antibody drugs to those with new coronary pneumonia or those who have recently become infected.

  "China News Weekly" No. 24, 2020

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