China Kexing "fights again" the new crown, can broad-spectrum antibodies open up a new situation for "ending the epidemic"?

COVID-19 caused by the coronavirus (SARS-CoV-2) infection has caused the world to suffer a once-in-a-century public health crisis, and the world has launched three paths to stop the spread of the new crown virus: non-medical public health prevention and control measures, vaccine development, and drug search

In the early stages of the epidemic, the malaria treatment drug hydroxychloroquine, the antibacterial drug azithromycin, and a variety of antiviral drugs that are not aimed at the new crown virus were first seen, bringing hope

Subsequent small molecule drugs have led to real advances

A new study published this month in the New England Journal of Medicine (NEJM) showed that oral antiviral nirmatrelvir was able to significantly reduce the risk of hospitalization and death in ≥ 65-year-olds with COVID-19, although this benefit

The S protein is an important structure for viruses to infect cells and induce neutralizing antibodies (Source: Cellular & Molecular Immunology)

Monoclonal antibody products are another research route for researchers to fight SARS-CoV-2, and so far a number of neutralizing antibody products targeting S proteins have entered the clinical trial stage, some of which have been authorized for emergency use (EUA) or approved for marketing

However, compared with small molecule drugs, neutralizing antibody drugs have strong targeting and long-lasting efficacy; And compared with plasma therapy, neutralizing antibodies have obvious large-scale production advantages

However, compared with small molecule drugs, neutralizing antibody drugs have strong targeting and long-lasting efficacy; And compared with plasma therapy, neutralizing antibodies have obvious large-scale production advantages

New neutralizing antibody cocktail therapy, highly effective broad-spectrum long-lasting, prevention and treatment in one

New neutralizing antibody cocktail therapy, highly effective broad-spectrum long-lasting, prevention and treatment in one

On August 4th, the latest paper published by Xie Xiaoliang/Cao Yunlong of the Biomedical Frontier Innovation Center (BIOPIC) of Peking University, Xiao Junyu Research Group of the School of Life Sciences of Peking University, and Jin Ronghua of Beijing Ditan Hospital in the pre-print website bioRxiv brought a major breakthrough in the field of new crown neutralizing antibody research and development, which is expected to change the two neutralizing antibodies in

It is expected to change the field of prevention and control of the two neutralizing antibodies into the field of

Because the virus is not easy to mutate at the binding site of SA58/SA55, it is difficult for SA58/SA55 to escape, which brings new hope

Source: bioRxiv

Antibodies are a key component of the fluid adaptive immune response and are one

In this latest study, the scientists first proposed the "four criteria" for identifying antibodies that are not easily escaped by viral mutations and have strong neutralizing activity: 1) Select the antibodies that are effective against existing mutant strains and have the highest neutralizing activity; 2) Try to form an antibody cocktail that neutralizes epitopes without overlapping; 3) Neutralizing antibodies targeting conservative sites on Sabé virus RBD are selected, and these epitopes need to be associated with the key functions of the virus; 4) The antibody-targeted RBD epitope should belong to the rare epitope of SARS-CoV-2, thus avoiding immune stress screening

In this latest study, the scientists first proposed the "four criteria" for identifying antibodies that are not easily escaped by viral mutations and have strong neutralizing activity:

However, finding candidate neutralizing antibodies that meet these four criteria is not an easy task

Previously, scientists proposed a high-throughput unsupervised epitope mapping technique based on deep mutation scanning (DMS), which can perform epitope distribution and escape mutation analysis more efficiently than traditional epitope classification techniques

The researchers combined high-throughput single-cell VDJ sequencing (scVDJ-seq) techniques or reverse transcription PCR (RT-PCR) to establish a highly efficient method to isolate large numbers of neutralizing antibodies while identifying their binding epitopes

Identification of broad-spectrum Sabé virus neutralizing antibodies (source: biorxiv)

With this innovative approach, the researchers collected about 13,000 memory B cells from 28 SARS survivors who had received three doses of COVID-19 vaccine, and collected 2838 antibody sequences in them, of which 1413 (containing IgG1 heavy chain constant regions) were expressed in vitro, and finally screened out 286 antibodies

Through detailed epitope analysis, escape mutation profiling studies, and cryo-EM structural analysis, the final "SA58 (BD55-5840)" and "SA55 (BD55-5514)" were rationally selected as the final non-competitive neutralizing antibody combination (cocktail) that exhibited extraordinary SARS-CoV-2 neutralizing breadth and potency
.

The final "SA58 (BD55-5840)" and "SA55 (BD55-5514)" were rationally selected as the ultimate non-competitive neutralizing antibody combination (cocktail) that exhibited extraordinary SARS-CoV-2 neutralizing breadth and potency
.

Further studies have shown that the SA55/SA58 antibody combination can effectively neutralize the SARS-CoV-2 Omicron variant constructed by all researchers, indicating that it has a significant tolerance to escape mutations
.

It shows significant tolerance to escape mutations
.

To evaluate the therapeutic and prophylactic effects of the SA55/SA58 antibody combination on SARS-CoV-2, the researchers used infectious SARS-CoV-2 Omicron BA.
1 strain infection to express human ACE2 (hACE2) transgenic mice
.
The prevention and treatment groups injected 20 mg/kg of SA55/SA58 antibody combination intraperitoneally 24 hours before infection and 2 hours after infection, respectively; To test the stability of different antibody delivery routes, an additional group of prevention mice is presented by intramuscular injection (IM) SA55/SA58 antibody combination
.
Mice in the control group are injected with phosphate-buffered saline (PBS
).
5 mice per group, monitor and record the body weight
of each group of mice daily.
All mice are euthanized on day 3, lung and tracheal tissue are taken for viral load analysis
.

Therapeutic prophylaxis

SA55/SA58 has a strong protective effect on mice (Source: biorxiv)

The results of the study showed that the control group mice had significantly higher
lung and tracheal viral RNA copies compared to all prevention and treatment groups.
In contrast, all but one mouse in the prevention group (IM) had no viral RNA
detected in the lungs and trachea of all other mice in the prevention and treatment groups.
Notably, the only mice infected with BA.
1 showed only mild symptoms and did not cause significant weight changes
.
Therefore, overall, the SA55/SA58 antibody combination shows a strong virus clearance and blocking effect
in vivo.

The SA55/SA58 antibody combination exhibits strong virus clearance and blocking effects
in vivo.

At the same time, the study mentioned that by modifying the Fc region of the neutralizing antibody, the half-life of the antibody can be extended to 90 days, and the modification may provide effective protection
for up to half a year.

By modifying the Fc region of the neutralizing antibody, the antibody half-life can be extended to 90 days

Overall, the SA55/SA58 neutralizing antibody combination has the characteristics of high efficiency, broad spectrum, anti-escape and long-lasting effect, and has a strong neutralization activity for current Omicron variants, including BA.
1, BA.
2, BA.
2.
12.
1 and BA.
4/BA.
5; in addition, it has strong application potential at both ends of the prevention and treatment, especially for people with special health conditions, so it is a very valuable candidate for neutralizing antibody drugs
.

The COMBINATION OF SA55/SA58 neutralizing antibodies combines high efficiency, broad spectrum, anti-escape and long-lasting effects at both ends of the spectrum, especially for people with special health conditions

Since the outbreak of the new crown epidemic, Chinese scientists have continued to make breakthroughs

Since the outbreak of the new crown epidemic, Chinese scientists have continued to make breakthroughs

In fact, since the outbreak of the new crown epidemic in early 2020, Chinese scientists have continuously tackled key problems in virus genome sequencing, vaccine research and development, and analysis of virus escape mechanisms, and have achieved a large number of world-leading research results
.
During this period, a number of outstanding research teams and cooperative groups have also emerged
.

During this period, a number of outstanding research teams and cooperative groups have also emerged
.

Before the development of SA55/SA58 neutralizing antibody combinations, Academician Xie Xiaoliang's team and his collaborators decided to carry out research on the development of new crown therapy, mechanism analysis, virus escape and other aspects from the beginning of 2020, and have published many papers
in top journals such as Cell, Nature, cell research and so on.
Among them, in the research and development of neutralizing antibodies, as early as May 2020, Academician Xie Xiaoliang's team and his collaborators took the lead in publishing papers in Cell Journal, innovatively using high-throughput single-cell sequencing technology to screen neutralizing antibodies
.

Previously, it took months or even years to find neutralizing antibodies using single-cell cloning amplification methods, but in recent years, single-cell genome technology has developed rapidly, including single-cell expansion technologies such as MALBAC and LIANTI invented by Academician Xie Xiaoliang, which has greatly improved the throughput and accuracy of single-cell analysis, making it possible to quickly find neutralizing antibodies, which can shorten the search time from years to months, and greatly improve
efficiency.

In August 2021, in a Cell Research paper, the research collaboration reported neutralizing antibody combinations that exhibited pM-level activity on alpha, Beta, Kappa, Delta, and other mutant strains
.
In December of the same year, scientists published a paper in the journal Nature that revealed the mechanism
by which Omicron escapes RBD-targeting neutralizing antibodies.
In June this year, the collaborative team published the world's first research paper on the structure and humoral immune escape characteristics of BA.
2.
12.
1 and BA.
4/5 spike proteins in Nature Magazine, revealing the molecular mechanism of the "immunogenic sin" of the Omicron variant, and successfully constructed a comprehensive database
of new coronavirus RBD antibody binding epitope, escape map, and neutralization activity.

The new results published at bioxiv are another milestone
achieved by Chinese scientists in the field of new crown neutralization antibody research and development based on previous research experience.
SA55/SA58 neutralizing antibody cocktail therapy shows high potency, broad spectrum, anti-escape ability, long-term protection ability and prevention and treatment "two-in-one" characteristics, which is expected to bring new opportunities
for the development of new crown "special drugs" and winning the new crown epidemic prevention war.

The new results published at bioxiv are another milestone
achieved by Chinese scientists in the field of new crown neutralization antibody research and development based on previous research experience.

Overcome the problem of mutant strain escape and open up a new situation for ending the COVID-19 pandemic

Overcome the problem of mutant strain escape and open up a new situation for ending the COVID-19 pandemic

In addition to the outstanding team of scientists, in this new crown epidemic prevention and control battle, there are also many domestic companies that stand out, such as China Kexing
, which leads the development of the COVID-19 vaccine, which is the first in the world to enter phase III clinical research.

From the unhesitating launch of the research and development of the new crown vaccine in early 2020, to the inactivated new crown vaccine Kellyford taking the lead in obtaining national approval for emergency use in June 2020, to the conditional listing of Kerraffle in February 2021, and being included in the WHO's emergency use list in June of the same year, China Kexing handed over a report card
of global praise together with multinational research teams including Brazil, Turkey and Indonesia in the "first battle" against the new crown 。 As the Aumecreon mutation spreads around the world, China Kexing also took swift action, and after obtaining samples of the Aomi kerong mutation in December 2021, it launched a clinical study in Hong Kong, China in April 2022 to actively promote the development of a new coronavirus vaccine for
the Omiljung strain.

In the "first battle" against the new crown, China Kexing, together with multinational research teams including Brazil, Turkey and Indonesia, handed over a report card
that won global praise.

The newly discovered SA55/SA58 neutralizing antibody combination has been transferred by the research team to China Kexing, and it is expected to submit a clinical application
to the State Drug Administration in December 2022.
China Kexing, which has been deeply involved in the field of vaccine research and development for many years, this layout neutralizing antibody cocktail therapy is a "new step" in the prevention and treatment of the new crown under the still unpredictable situation of the new crown epidemic
.
At present, vaccines, small molecule drugs, and neutralizing antibody drugs are playing different roles
in the fight against COVID-19.
As an important part of the prevention and treatment of new crown, neutralizing antibodies have unique advantages, including providing long-term protection with one injection, making up for the lack of use of vaccines in immunely vulnerable populations, and playing a key preventive role in people with vaccine contraindications
.

The research team has been transferred to China Kexing and is expected to submit a clinical application
to the State Drug Administration in December 2022.
A "new step" in the fight against COVID-19
.

More than two years after the outbreak of the new crown epidemic, the trend of the virus raging around the world has not subsided, and countless teams in the global scientific and industrial circles are racing against the clock to strive for breakthroughs
.
With the catastrophic impact of the SARS-CoV-2 variant on the effectiveness of existing vaccines and drugs, the development of new vaccines and drugs that can benefit a wider group while being highly tolerant of the variants has become a key "proposition"
in the field of COVID-19 prevention and control.
If neutralizing antibody combinations such as SA55/SA58 can be successfully marketed, they will not only greatly fill the prevention gap of existing vaccines, but also be expected to change the treatment pattern of COVID-19 and may become the next "blockbuster product"
in the field of new crown.

If neutralizing antibody combinations such as SA55/SA58 can be successfully marketed, they will not only greatly fill the prevention gap of existing vaccines, but also be expected to change the treatment pattern of COVID-19 and may become the next "blockbuster product"
in the field of new crown.

We expect that based on China Kexing's long-term cognitive accumulation of the new crown virus, rich experience and resources for international clinical research cooperation, as well as sufficient financial and technical support, this world-leading innovative neutralizing antibody cocktail therapy can successfully move to the clinic as soon as possible, overcome the problem of escape of new coronavirus strains, and open up a new situation
for ending the new crown pandemic.

It can successfully go to the clinic as soon as possible, overcome the problem of escape of the new crown mutant strain, and open up a new situation for ending the new crown pandemic

Related Papers:

Related Papers: Related Papers:

[1] Yunlong Cao et al.
Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents.
biorxiv(2022).

[1] [1] Yunlong Cao et al.
Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents.
biorxiv(2022).

[2] Yunlong Cao et al.
Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients’ B Cells.
Cell(2020).

[2] [2] Yunlong Cao et al.
Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients’ B Cells.
Cell(2020).

[3] Shuo Du et al.
Structures of SARS-CoV-2 B.
1.
351 neutralizing antibodies provide insights into cocktail design against concerning variants.
Cell Research(2021).

[3] [3] Shuo Du et al.
Structures of SARS-CoV-2 B.
1.
351 neutralizing antibodies provide insights into cocktail design against concerning variants.
Cell Research(2021).

[4] Yunlong Cao et al.
Omicron escapes the majority of exi

[4] [4] Yunlong Cao et al.
Omicron escapes the majority of exi