Another shield against the new crown!

Recently, the new crown epidemic in many provinces and cities in China is very fier.
The first is Jilin's "prohibition of inter-provincial and inter-regional flow", and then Shanghai's "global static managemen.
According to the data released by the Shanghai Municipal Health Commission, from February 26 to May 6 this year, a total of 55,384 local confirmed cases (over 600,000 positive infections) and 7,699 were treated in hospital (including 464 severe cases and critically ill case.
Type 87 cases), 528 cases died [
When summarizing the characteristics of death cases, we found that almost all patients were complicated with severe multi-organ underlying diseases including advanced malignant tumor, severe cardiovascular disease, diabetes, chronic kidney disease, e.
, and were in critical conditi.
This also suggests that those infected who have progressed to severe disease should start antiviral treatment as soon as possib.
According to the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 9) [2], the combination of neutralizing antibody ambavirumab/romisevirumab and the small molecule drug Paxlovid is recommended for mild and common types, and Adults with high risk factors for progression to severe disea.
However, it should be noted that the ninth edition of the "Diagnosis and Treatment Protocol" clearly pointed out that the instructions should be read carefully before using Paxlovid, and it should not be cleared with meperidine, ranolazine and other highly dependent CYP3A, and its plasma concentration will lead to severe and/or severe or drug combination with life-threatening adverse reactio.
In fact, the use of Paxlovid is not recommended for patients with severe hepatic and renal insufficiency (eGFR<30ml/min, or Child-pugh class .
The long-acting neutralizing antibody ambavirumab/romisevirumab, which is not directly metabolized by the liver and kidney, does not have such a probl.
New coronavirus under the electron microscope (Source: NIAID-RML) In addition, although vaccination can significantly reduce the risk of severe illness and death, some special groups cannot be protected because they cannot be vaccinated or respond poorly to vaccin.
For example, patients with allergies to vaccine components or severe adverse reactions are not suitable for vaccination; for patients with immunosuppression (such as long-term use of immunosuppressive drugs, organ transplantation, hematological and solid tumors under treatment), They respond poorly to the vaccine, have very low neutralizing antibody titers after vaccination, and remain at high risk of infection [4,
Therefore, the above-mentioned vulnerable groups have a higher risk of infection and severe disea.
Long-acting neutralizing antibodies are undoubtedly the best choice for the treatment of diseases or prevention of infecti.
So what exactly are long-acting neutralizing antibodies? Why can kidney function not be considered during application, and why can it play the role of treating and preventing new crown infection at the same time? To fundamentally understand these problems, we have to start with the structure of antibodies and the way they are metaboliz.
Understanding the Metabolism of Antibodies from the Structure of Antibodies Antibodies are an important part of the human immune syst.

Humans only discovered its existence in the 1890s, and scientists did not know that only lymphocytes can produce antibodies until the 1960s [
Nearly half a century of scientific research results tell us that there are five types of antibodies in the human body: IgA, IgD, IgE, IgG and I.

Among them, IgG antibodies account for the highest proportion, accounting for about 85% of the total antibodies in serum; the concentration is the highest, up to 5–15 mg/mL; the half-life is the longest, with an average of 23 days [
The basic characteristics of the five major classes of antibodies in the human body [7] Currently, the antibodies used in clinical treatment are mainly IgG class antibodies, and the neutralizing antibodies for the treatment or prevention of new coronary pneumonia are also IgG class antibodi.

Therefore, the following content mainly focuses on IgG class antibodi.

Expa.
Structurally, IgG antibodies are composed of four polypeptide chains, two long heavy chains (h) and two short light chains (l), which together form a "Y"-shaped structu.

Schematic diagram of the structure of IgG class antibodies [7] From a functional point of view, IgG antibodies can be divided into two parts: the two arms of the upper half of "Y" are antigen-binding fragments (Fab), which are responsible for recognizing and binding antigens, such as binding to the new coronavirus S protein The Fab part of the neutralizing antibody is the Fab part of the neutralizing antibody; the lower part of "Y" is the crystallizable fragment (Fc), although this part does not bind to the antigen, it mediates a variety of biological effects and is closely related to the half-life of the antibo.

From the distribution point of view, IgG is a polar macromolecular protein, and they enter different organs and tissues from the circulatory system through convection and receptor-mediated transcellular transport [
Some researchers have systematically analyzed the distribution of IgG antibodies in different tissu.

They found that the concentration of IgG in the lung is relatively high, about 19% of the plasma concentration, about 12% in the heart, and about 17% in the kidn.

[
In terms of metabolism, as a macromolecular protein, the clearance of IgG does not require metabolism by the hepatic cytochrome enzyme system, so it has no interaction with related drugs [9]; IgG is not filtered or secreted by the kidney, but is mainly Tissue endothelial cells or monocytes take up and decompose and clear [1
As early as the 1960s, .

Roger Brambell proposed a mechanism of antibody metabolism, and he believed that receptors located in cellular compartments and/or on the cell surface could protect IgG antibodies from being catabolized [11, 1
In 1989, Neil.

Simister and Keith.

Mostov finally cloned the receptor that protects IgG antibodies, which is the neonatal Fc receptor (FcRn) [1
After 20 to 30 years of research, the mechanism of FcRn protecting IgG antibodies has been basically clarifi.
Specifically, IgG antibodies in blood are taken up by endothelial cells or monocyt.

After entering cells, IgG antibodies bind to FcRn in acidic (at pH 6-5) endosomes (millimolar or nanomolar level.

low affinity), protected from degradation by lysosomes; IgG that is not bound to FcRn (due to competition from other IgGs) will enter lysosomes for degradation; IgG antibodies bound to FcRn are subsequently transported to the cell surface, where they encounter In a physiological environment (pH around 4), IgG antibodies are separated from FcRn, and IgG antibodies are re-released into the interstitial fluid or blood [1
The mechanism by which FcRn regulates IgG metabolism [15] Theoretically, through the binding of FcRn to IgG, the balance of IgG in the body can be regulated: when IgG exists in large quantities, IgG-binding FcRn tends to be saturated, and IgG that cannot bind to FcRn will be destroy.

Lysosomal degradation, and when the IgG concentration is low, the binding of IgG to FcRn is preserved [14, 1
This is why the average half-life of IgG antibodies can be as long as 23 da.

Animal experiments have shown that FcRn deficiency can shorten the half-life of IgG in mice from 6-8 days to 1 day [1
It can be said that cells expressing FcRn are actually regulators of IgG antibody leve.

Although the glycosylation, charge and isoelectric point (pI), target-mediated drug disposition (TMDD), and anti-drug antibody (ADA) of IgG antibodies also affect the metabolism of antibodies, FcRn is the most critical and The most studied IgG antibody metabolic regulator [1
Stronger affinity and longer half-life In recent years, scientists have done a lot of research on the amino acid sequence of the Fc segment of IgG antibodies, trying to find the key amino acids that affect the affinity of IgG antibodies to Fc.
Relevant studies have shown that various mutations such as T250Q/M428L, V308P, M428L, M252Y/S254T/T256E (YTE), M428L/N434S (LS), N434A and N434H in the Fc segment of IgG antibodies can be released at pHImprove the affinity of the modified IgG and FcRn, and ensure that the separation of the two under physiological pH conditions is not affect.

In vivo experiments of these mutants have shown that they can prolong the terminal half-life of engineered therapeutic antibodies in cynomolgus and rhesus monkeys by 2-4 times [1
The prolongation of the half-life means that the blood drug concentration can be maintained at a high level for a long time, and the long-term stability of the blood drug concentration also means that the neutralizing antibody concentration in the lungs of the target organ will also be maintained at a high level for a long ti.

It is very valuable for the treatment and prevention of diseas.

Studies have shown that prolonging the half-life of antibodies will make their effects more durable [16-1
Of all the Fc mutation types mentioned above, YTE is one of the most studied and widely used forms of mutati.

For example, the respiratory syncytial virus (RSV) neutralizing antibody Nirsevimab (MEDI8897) has been YTE-engineer.

Preclinical studies have shown that the introduction of YTE mutation into the Fc segment of Nirsevimab increases the half-life in cynomolgus monkeys by more than 3 times compared with the original antibody [1
Two clinical studies have shown that the average half-life of Nirsevimab in the human body is about 60 days [20, 21], which is about 3 times the average half-life of common IgG antibodies [
Most importantly, the YTE-engineered antibody in the Fc segment can provide durable and effective protecti.
For example, a single injection of Nirsevimab reduces the risk of RSV infection in preterm/term infants seeking medical attention by more than 70%, and this protection lasts for at least 150 days [20, 2
Long-acting antibodies, long-term protection Similarly, the Fc segment of Ambavirumab/Romisevirumab, the only approved anti-COVID-19 antibody combination in China, has also undergone YTE transformati.

After the modification, the half-life of ambavirumab/romisevirumab in the human body is extended to 46-76 days, which is 2-3 times that of ordinary IgG antibodies[2
This change also significantly increased the concentration and exposure of ambavirumab/romisevirumab in the lungs of target organs, which can maintain antiviral activity for a long time, which also maintains their resistance to the new coronavirus to a certain exte.

Resistance of mutan.

It can be seen from this that Ambavirumab/Romisevirumab, which has a long-acting half-life, is expected to provide long-term protection to immunocompromised infected patients while treating infections, and reduce their recurrence rate within a certain period of ti.

risk of infecti.

In addition, the long half-life also provides the basis for clinical studies (in progress) of this combination post-exposure and pre-exposure prophylax.

Like ambavirumab/romisevirumab, the Fc segment of Evusheld (Tixagevimab/Cilgavimab) pair of neutralizing antibodies has also been modified by YTE [23], and their half-life in the human body is as long as 9 days or so [2
On the 20th of last month, a research team led by Mark.

Esser published detailed clinical data of the neutralizing antibody combination Tixagevimab/Cilgavimab for pre-exposure prevention of new coronary pneumonia in the New England Journal of Medicine [2First look at the demographic characteristics of the subjects enrolled in this study [23]: their mean age was 55 years, and 44% of the subjects were 60 years or older; 75% of the subjects were It is believed that there is a higher risk of severe illness after infection with the new cro.

The results showed that compared with placebo, the Tixagevimab/Cilgavimab combination reduced the risk of symptomatic infection of the new crown by 88% at 6 months of follow-up [2
This means that a single injection of Tixagevimab/Cilgavimab combination can provide immune protection for at least 6 months in high-risk groups [2
It is based on the above data that Tixagevimab/Cilgavimab has been approved by FDA and EMA for pre-exposure prophylaxis of new coronary pneumonia[25,2
Applicable people: people with moderate to severe impairment of immunity due to medical reasons, or who are unable to develop an adequate immune response to the new crown vaccine due to immunosuppressive drugs or treatment; A history of adverse reactions (such as severe allergic reactions), and it is not recommended to receive any approved or authorized new crown vaccine [2
In general, the YTE transformation of the Fc-segment of anti-new coronavirus neutralizing antibodies has greatly extended the half-life of neutralizing antibodies, making them capable of potent treatment and long-term prevention of new coronavirus infecti.

In the future, long-acting neutralizing antibodies will become a powerful supplement to vaccines, providing long-term immune protection to high-risk groups who cannot be vaccinated or who have a low response to vaccin.
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https:// [2
https:// Author of this articleBioTalkereuro.

eu/en/news/ema-recommends-authorisation-covid-19-medicine-evusheld Author of this article BioTalkereuro.

eu/en/news/ema-recommends-authorisation-covid-19-medicine-evusheld Author of this article BioTalker