Antibody drug brings new hope for pandemic control
The constant resurgence of the pandemic combined with the emergence of new variants urgently require new solutions
By Ji Jing  ·  2021-12-31  ·   Source: NO.1 JANUARY 6, 2022
Zhang Linqi (third right) and his team on March 2, 2020

Though China's COVID-19 vaccination rate has surpassed 80 percent, those who had been vaccinated were not spared during the country's most recent epidemic upsurges.

In Shaanxi Province's most recent outbreak, 831 cases were reported between December 9 and 27, mostly in the provincial capital of Xi'an. To prevent the spread of the epidemic, Xi'an entered a lockdown on December 23, becoming the second city with a population of over 10 million to have been locked down since late 2019, when the coronavirus was first reported in Wuhan, capital of Hubei Province.

The constant resurgence of the pandemic combined with the emergence of new variants urgently require new solutions and on December 8, China granted emergency approval for its first antibody combination therapy for COVID-19 treatment.

The drug consists of two neutralizing antibodies separated from the serum of recovered COVID-19 patients. It enters the patient's body via an intravenous drip. Clinical trial data show the medicine can reduce both the hospitalization and death rates of high-risk COVID-19 outpatients by 80 percent, and has further proven to be effective against the latest variants. As it can reside in the body for nine up to 12 months, it can also serve to prevent further infections.

Grueling efforts

Zhang Linqi, a professor and Director of the Global Health and Infectious Diseases Research Center and Comprehensive AIDS Research Center at Tsinghua University's School of Medicine, has been in charge of the new drug's research and development.

The 58-year-old is a renowned virology scholar. After graduating from the department of biology at Beijing Normal University, he pursued his PhD in HIV/AIDS studies at the University of Edinburgh in the UK. In 1993, he went to New York University in the U.S. to continue his studies on the virus. In 2007, he returned to China to conduct research on HIV/AIDS drugs and vaccines at Tsinghua University. He has further studied highly pathogenic viruses such as Ebola and Middle East Respiratory Syndrome.

In January 2020, Zhang led a research alliance developing an antibody treatment for COVID-19, linking his team from Tsinghua University's School of Medicine with a research group from the university's School of Life Sciences managed by Professor Wang Xinquan and a team directed by Professor Zhang Zheng from the Third People's Hospital of Shenzhen in Guangdong Province.

The key was to study the structure and function of the coronavirus spike protein, a multifunctional molecular machine that mediates coronavirus entry into host cells. "The spike proteins are like the key for a thief to enter a room. The lock is the human cell formation. The virus enters through interactions of the spike proteins with proteins on the surface of human cells and these cells in turn serve as the base for virus replication," Zhang Linqi explained.

Antibodies are the natural defense mechanisms of the human body. Zhang Linqi and his team have aimed to uncover one or more super antibodies that can stop the virus from entering the cells for replication and infection. These antibodies can help fight the virus and improve patient immunity to enable their recovery.

The human body produces antibodies in response to an infection. However, of these, only neutralizing antibodies are capable of stopping the virus. "Our task is to select these special antibodies and inject them into the patients to halt transmission. This is how antibody drugs work," Zhang Linqi said.

To find the antibodies against the virus, researchers need to have access to those of a certain number of patients. The task of collecting these antibodies was undertaken by Zhang Zheng's team. The team completed gene sequencing of antibodies produced by COVID-19 patients, from thousands selected 206 excellent antibody genes and provided these to Zhang Linqi's team.

"With the genes, we first need to check if these antibody proteins can bind with the virus. In addition to binding with the virus, the proteins also need to have the ability to stop the virus from entering human cells," Zhang Linqi said.

After more than one month of research, Zhang Linqi's team finally screened two antibodies

possessing strong capabilities to stop the virus.

But there was a deeper reason behind the selection of two antibodies. "Both my colleagues and I have been researching HIV/AIDS and we have a feeling that SARS-CoV-2 is not easy to control. Although the virus belongs to a different category of HIV/AIDS, both are ribonucleic acid (RNA) viruses. One characteristic of RNA viruses is that they are highly susceptible to mutation," Zhang Linqi said.

Therefore, the team decided to select two antibodies which were able to coordinate with each other to combat the virus.

The treatment was first tested on animals for safety and efficiency purposes. Then the Phase I clinical trial of the treatment on humans was completed in September 2020. However, just two months later, in December 2020, the first variant of SARS-CoV-2 was discovered.

Zhang Linqi said they were worried that the antibodies might not be as effective in combating the new variant. They conducted an evaluation of the antibodies' ability to deal with the variant and found that they still proved effective.

International trial

At the time when Zhang Linqi's team planned to carry out Phase II and III clinical trials of the antibodies, there were hardly any COVID-19 cases on the Chinese mainland thanks to China's epidemic response measures. In December 2020, the team applied to join a clinical trial led by the U.S. National Institute of Health (NIH).

As the drug demonstrated good safety and efficacy results in the Phase I clinical trial, it received approval from the NIH to begin the Phase II international clinical trial.

The NIH carried out the Phase III trial across 111 trial bases in six countries covering four continents. "So the process is up to strict international standards," Zhang Linqi said.

On December 3, 2021, after a near one-year wait, the NIH published all the clinical data from the trials. The data showed that in the Phase III clinical trial, compared with the group using a placebo, the group treated with the medicine developed by Zhang Linqi's team saw its hospitalization and death rates reduced by 80 percent. By the end of the 28-day trial, the group treated with the medicine reported zero deaths, while that using a placebo reported nine.

"The results are exhilarating. It shows the two antibodies we selected are effectual," Zhang Linqi said.

However, since December 2021, the Omicron coronavirus variant has spread across the world. Whenever a new variant appears, Zhang Linqi's team needs to reevaluate the efficacy of the antibodies. They found that one antibody had partially lost its ability to fight to the new variant, while the other had maintained its effectiveness. Using the two antibodies in conjunction with one another has maintained the treatment's ability to neutralize the Omicron variant.

Although the treatment has already been approved by Chinese authorities, Zhang Linqi's team hasn't stopped researching. They are further studying the interaction mechanism between the virus and antibodies and the rules of the virus's mutation to look for better and backup antibodies for fear they might lose their effect against future variants.

Internationally, the U.S. Food and Drug Administration (FDA) authorized American pharmaceutical company Merck's oral antiviral for the treatment of mild-to-moderate COVID-19 on December 23, 2021, the second pill approved for treating COVID-19 following the one from Pfizer. Merck's pill, called molnupiravir, is authorized for use in adults with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate, according to the FDA.

While antibody medicines bring new hope, Zhang Boli, a traditional Chinese medicine expert and President of the Tianjin University of Traditional Chinese Medicine, cautioned that the pandemic will not disappear because of a new treatment. Practice has proven that China's epidemic response system and the combination of the traditional Chinese and Western medicine are successful weapons against the virus. Thanks to the system, although there have been sporadic outbreaks of the epidemic from time to time, China has been able to clear the cases relatively quickly.

Copyedited by Elsbeth van Paridon & G.P. Wilson

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