[IBS 코로나19 리포트 시즌2] How far have you come to develop an antibody treatment for COVID-19: Dong-A Science

October last year. News spread around the world that former US President Donald Trump was confirmed for Corona 19. What was even more surprising was that after three days of treatment, he returned to the White House early. The public’s attention was focused on what kind of treatment was used to recover quickly. U.S. presidential medical staff officially announced that they were taking remdesivir, dexamethasone and an antibody treatment called’REGN-CoV-2′.

Remdesivir is the first and currently the only COVID-19 drug that was being developed through drug re-creation (see Corona 19 Science Report 1 Vol.6) to be approved by the US Food and Drug Administration (FDA). This drug was received (approved in October 2020). Remdesivir inhibits viral replication by binding to Sascoronavirus-2 RNA polymerase. It is being used in the treatment of corona19 patients along with dexamethasone, an immunosuppressant to prevent cytokine storms.

However, the therapeutic effect of remdesivir in the actual clinical field did not meet expectations. Moreover, various side effects such as vomiting, decreased liver and kidney function, rash, allergic reactions, and shortness of breath have been reported, and the need for new treatments is becoming more desperate. There is another substance to note in Trump’s treatment case. What on earth is an antibody treatment called’REGN-CoV-2′ that was used for the president’s treatment before it was even approved as a treatment?

Antibodies and Antibody Drugs

When foreign substances (antigens) such as bacteria or viruses penetrate into the body, antibodies are what the immune system creates in order to recognize, remember, and neutralize them. An antibody binds very precisely to a specific antigen. Our body is able to make a large repertoire of more than 1012 antibodies through gene rearrangement at the DNA level. As such, it can respond to various antigens and infectious substances.

Also, unlike other proteins in the body, antibodies have a long half-life in the body of 2 to 3 weeks. Due to these characteristics, various attempts are being made to make antibodies in large quantities in a laboratory rather than in a human body and use them for research, industry, and medical use (diagnosis, prevention, and treatment). The research of Dr. Georges Kohler and Dr. Chesar Milstein, who won the 1984 Nobel Prize in Physiology or Medicine, is representative. They succeeded in mass production of monoclonal antibodies for the first time through the development of a’hybridoma technology’ that fuses immune cells and cancer cells, and received the Nobel Prize for this achievement.

Subsequently, with the rapid development of molecular biology, various antibody-related technologies such as antibody mass production technology, antibody selection technology, and antibody improvement technology using the animal cell line CHO (Chinese Hamster Ovary) have appeared. In particular, the development of therapeutic antibodies has established itself as a major axis of the pharmaceutical industry. For example,’Humira (a treatment for immune diseases such as rheumatoid arthritis and Crohn’s disease)’, the world’s best-selling drug over the past five years, is also a therapeutic antibody. Domestic bio companies such as Samsung Biologics and Celltrion are also producing and developing antibody treatments.

In vivo antibodies have five isotypes, such as IgG, IgD, IgA, IgE, and IgM. Depending on the type, there are little differences in function and body function. IgG-type antibodies are the most common in the blood and are a common form of antibody therapy.

Until now, antibody treatments have been mainly developed for the treatment of cancer or immune diseases. Treatment strategies vary. There are strategies to treat diseases by binding to antigenic proteins and regulating cell signaling, and strategies to induce the death of cancer cells by attaching to the surface of cancer cells and activating the immune system. In addition, in recent years, by attaching a radioactive substance or an anticancer chemical drug to an antibody, a treatment strategy has been developed to deliver the substance only to cancer cells, through which only cancer cells are selectively killed.

Corona 19 antibody treatment,’sticky binding’ with Spike protein

In order to prevent virus or bacterial infection, vaccine development is a’gold standard’. After the genetic information of Sascoronavirus-2 was revealed, several biotechnology companies started developing vaccines quickly. Vaccines whose preventive effects have been confirmed through clinical trials have already been administered in the United States and Europe (see Corona 19 Science Report 2 Vol. 3-5).

Vaccines help prepare the body for antibodies to fight pathogens immediately after infection. If so, can we make an antibody to fight the virus outside and inject it into the body during infection? It is antibody drugs (prophylactic antibodies and antibody treatments) that have developed from this idea. Synagis, which blocks respiratory syncytial virus (RSV) infection, and Inmazeb, which blocks Ebola virus infection, are representative examples of antiviral antibody treatments. However, there are not many disadvantages of antibody therapy. As it takes a huge amount of time and money to find a successful treatment, pharmaceutical companies considering economic and marketability were reluctant to develop. Patients prefer simple medications over antibody treatments because they are expensive and inconvenient to administer in the form of injections. For this reason, chemical drugs such as Tamiflu were first developed as a treatment to prevent the growth of the virus. In addition, when vaccines are developed and population immunity is formed, the number of patients rapidly decreases, so the use of antibody treatments developed by pharmaceutical companies at high costs may be reduced.

However, the way to deal with Sascoronavirus-2, which has become a pandemic, is quite different. There is no time to discuss these advantages and disadvantages, economic feasibility, and marketability. Researchers around the world are developing antibodies that bind to the spike protein on the surface of Sascoronavirus-2 using cutting-edge science and technology. Currently, more than 10 antibody treatments are in clinical trials, and more than 150 antibodies are being developed worldwide.

Then, among the various proteins of Sascoronavirus-2, why is the spike protein as a target? Since the initiation of infection is the binding of ACE2 receptors present on the cell surface to the spike protein, it is a strategy to block well from the beginning. In other words, the COVID-19 antibody therapeutic agent specifically binds to the spike protein and neutralizes the virus to prevent invasion into the cell. In addition, antibody treatments attached to the virus surface can induce various immune responses such as virus removal and T cell immune response.

Receptor binding region (RBD) of spike protein is a key target for antibody therapy

The antibody therapy administered to former President Trump is’REGN-CoV-2′ of US pharmaceutical company Regeneron, which is currently at the forefront of antibody therapy in the world.

Corona 19 antibody treatment (S309) neutralizes the virus by binding with the spike protein of Sascoronavirus-2. It is a strategy to prevent the binding of the ACE2 receptor and Spike protein in cells, which is the starting stage of infection.

Regeneron possesses’VelocImmune’ mice that have been engineered to make human antibodies as a core technology. Regeneron’s research team administered the receptor-binding domain (RBD) of the Sascoronavirus-2 spike protein to the mice, and selected antibodies that showed efficacy in neutralizing Sascoronavirus-2 infection among the generated antibodies. At the same time, antibodies that bind to the RBD of the Sascoronavirus-2 spike protein were also selected from B cells of patients who recovered after COVID-19 infection.

Two types of antibodies, REGN-10933 and REGN-10987, were finally selected by comprehensively considering the binding power, binding site, and neutralization power of the selected antibodies to the spike protein RBD. The mixture of these two antibodies in a cocktail form is REGN-CoV-2. REGN-CoV-2 is currently undergoing phase 3 clinical trials (Hansen et al., 2020).

Meanwhile, another pharmaceutical company, Vir Biotechnology, binds to the RBD of the Sascoronavirus-2 spike protein from the B cells of patients infected with SARS-CoV, which was popular in 2003, and shows efficacy in neutralizing virus infection. An antibody called’S-309′ was discovered (Pinto et al., 2020). Currently, a phase 3 clinical trial is underway with GlaxoSmithKline. It has been reported in the media that S-309-based antibody treatment candidates have signed a mass consignment production contract with Samsung Biologics in the early stages of development.

In fact, when analyzing antibodies in the blood of patients infected with COVID-19, among the spike proteins, antibodies that bind to RBD occupy a large part (Piccoli et al., 2020). In addition to RBD, research results are continuing to show that the N-terminal domain of Spike protein (NTD, N-terminal domain), and Nucleocapsis, which surrounds the genome inside the virus, can also be a major target for the development of neutralizing antibody therapeutics (Chi et al., 2020; DeFrancesco, 2020). Based on unprecedented rapid development and clinical trials, it is expected that several antibody treatments will be available in clinical use within this year, and more effective antibody treatments will continue to be developed.

Limitations and Complements of Antibody Therapy

Recently, there is high interest in mutant viruses introduced from the UK and South Africa. Fortunately, in the case of a vaccine, it is thought that the possibility of affecting efficacy is relatively small even if a mutation occurs in the spike protein. So, what about antibody treatments? Will the candidate antibody treatments developed so far be effective for variants of Sascoronavirus-2?

The biggest feature of monoclonal antibodies is that they bind strongly to only a specific site (Epitope) of one antigen. In other words, if there is a mutation in the position where the antibody should be attached, the binding power is bound to decrease. It means that the effect of neutralizing antibodies is inevitable.

To overcome this limitation, rather than using only one antibody, several neutralizing antibodies that recognize different parts of the virus spike protein are mixed to develop an antibody treatment in the form of a cocktail. Cocktail therapy is said to have high neutralizing power and decrease the probability of developing an escape mutant (Baum et al., 2020).

Another factor to consider in antibody therapy products is antibody-dependent enhancement (ADE). This is a phenomenon in which the neutralizing antibody binds to the Fc receptor of immune cells and rather helps virus infection, and is caused by low concentrations of immune serum or poor binding of antibodies and viruses (Arvin et al., 2020). In the case of dengue virus, respiratory syncytial virus (RSV), influenza, and SARS, there have also been reports of such antibody-dependent immunity enhancement, so care should be taken in the development of COVID-19 antibody treatments.

Fortunately, according to a recent study, it was found that the likelihood of antibody-dependent immunity enhancement after administration of COVID-19 antibody therapy is not very high (DeFrancesco, 2020). In order to maximize the efficacy of antibody therapeutics, the method of administration, dosage, and timing should be carefully reviewed, and it is necessary to ensure that the drug is well delivered to the lung tissue where the lesion is affected by Sascoronavirus-2 and activates immune cells. Enhancing the function of an effector and increasing the half-life in the body are also important considerations in the development of antibody treatments in the future.

Lastly, with the development of an antibody treatment for non-Spike protein, a Pan-coronavirus antibody treatment, chemical drugs that have fewer side effects and inhibit only Sascoronavirus-2 proliferation (RNA polymerase inhibitors, viral protein scissors) Inhibitors and viral assembly inhibitors) should also be developed.

From Chuseok to New Year’s Day. Two quiet holidays have passed. A ban on gatherings of 5 or more people was enforced, and restrictions on meetings and movements were increased so that the banner “People who are ineffective will come to their hometowns” is hung. It has become a world where you can’t imagine going out without a mask after a year of going through the mask riot. The ability to guess who is who just by looking at the eyes is gradually developing. Everyone’s mind is growing, hoping that the boring pandemic will end as soon as possible through the development of a COVID-19 vaccine and treatment. I look forward to seeing the smiles of people hidden under masks again on the coming Chuseok holiday.

※ References
Arvin, AM, Fink, K., Schmid, MA, Cathcart, A., Spreafico, R., Havenar-Daughton, C., Lanzavecchia, A., Corti, D., and Virgin, HW (2020). A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature 584, 353-363.

Baum, A., Fulton, BO, Wloga, E., Copin, R., Pascal, KE, Russo, V., Giordano, S., Lanza, K., Negron, N., Ni, M., et al. . (2020). Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014-+.

Chi, X., Yan, R., Zhang, J., Zhang, G., Zhang, Y., Hao, M., Zhang, Z., Fan, P., Dong, Y., Yang, Y., et al. (2020). A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science 369, 650-655.

DeFrancesco, L. (2020). COVID-19 antibodies on trial. Nat Biotechnol 38, 1242-1252.
Hansen, J., Baum, A., Pascal, KE, Russo, V., Giordano, S., Wloga, E., Fulton, BO, Yan, Y., Koon, K., Patel, K., et al. . (2020). Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 369, 1010-1014.

Piccoli, L., Park, YJ, Tortorici, MA, Czudnochowski, N., Walls, AC, Beltramello, M., Silacci-Fregni, C., Pinto, D., Rosen, LE, Bowen, JE, et al. (2020). Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology. Cell 183, 1024-1042 e1021.

Pinto, D., Park, YJ, Beltramello, M., Walls, AC, Tortorici, MA, Bianchi, S., Jaconi, S., Culap, K., Zatta, F., De Marco, A., et al . (2020). Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 583, 290-295.

Whittaker, GR, and Daniel, S. (2020). Going back in time for an antibody to fight COVID-19. Nature 583, 203-204.

Homin Kim, Institute of Basic Science (IBS) Biomolecule and Cell Structure Research Center CI‧KAIST Graduate School of Medical Sciences Associate Professor (Protein Structural Biochemistry)Hyunjoo Noh, Researcher at IBS Biomolecule and Cell Structure Research Center

※ Source of original text: Institute for Basic Science

The Institute of Basic Science (IBS) publishes a series of’Corona 19 Science Report 2’to seek scientific understanding of SARS-CoV-2 and ways to overcome it, following last year. In this series, we will focus on research trends and issues related to the development of vaccines and treatments, as well as viral mutations that have recently aroused global interest. We hope that the front-line knowledge and information delivered by IBS scientists and domestic experts will help end coronavirus infection-19 (COVID-19, hereinafter referred to as COVID-19).

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