How long-acting neutralizing antibodies can achieve lasting protection against COVID-19?
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How long-acting neutralizing antibodies can achieve lasting protection against COVID-19?
When summarizing the characteristics of death cases in many cities, Scientists found that almost all the patients were complicated with severe multi-organ underlying diseases including advanced malignant tumor, severe cardiovascular disease, diabetes, chronic kidney disease, etc. , and were in critical condition.
This also suggests that those infected who have progressed to severe disease should start antiviral treatment as soon as possible.
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 disease.
However, it should be noted that the instructions should be read carefully before using Paxlovid, and it should not be used in combination with drugs such as meperidine and ranolazine that are highly dependent on CYP3A clearance, and whose plasma concentration increases can lead to serious and/or life-threatening adverse reactions. .
In fact, the use of Paxlovid is not recommended for patients with severe hepatic and renal insufficiency (eGFR<30ml/min, or Child-pugh class C). The long-acting neutralizing antibody ambavirumab/romisevirumab, which is not directly metabolized by the liver and kidney, does not have such a problem.
The new coronavirus under the electron microscope (Source: NIAID-RML)
How long-acting neutralizing antibodies can achieve lasting protection against COVID-19?
In addition, while vaccination can significantly reduce the risk of severe illness and death, some special groups are not protected because they cannot be vaccinated or respond poorly to vaccines.
For example, patients who are allergic to vaccine components or have 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 [4,5].
Therefore, the above-mentioned vulnerable groups are at higher risk of infection and severe disease. Long-acting neutralizing antibodies are undoubtedly the best choice for the treatment of disease or prevention of infection .
So what exactly are long-acting neutralizing antibodies? Why can the kidney function not be considered in the application, and why can it play the role of treating and preventing COVID-19 infection at the same time? To fundamentally understand these problems, we have to start with the structure of antibodies and the way they are metabolized.
Understanding the Metabolism of Antibodies from the Structure of Antibodies
Antibodies are an important part of the human immune system. Humans only discovered its existence in the 1890s. It was not until the 1960s that scientists knew that only lymphocytes could produce antibodies [6].
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 IgM. 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 9.5–12.5 mg/mL; the half-life is the longest, with an average of 23 days [7].
The basic characteristics of five types of antibodies in the human body[7]
At present, the antibodies used in clinical treatment are mainly IgG- type antibodies, and the neutralizing antibodies for the treatment or prevention of COVID-19 pneumonia are also IgG-type antibodies . Therefore, we mainly focus on IgG-type antibodies in the following content.
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 structure.
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 the binding antigen. For example, the Fab part of the neutralizing antibody that binds to the S protein of the new coronavirus ; 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 antibody .
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 [7].
Some researchers have systematically analyzed the distribution of IgG antibodies in different tissues. They found that the IgG concentration in the lung is relatively high, about 14.9% of the plasma concentration , about 10.2% in the heart, and about 13.7% in the kidney. [8].
From a metabolic point of view, 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 kidneys, but is mainly absorbed by the kidneys. Tissue endothelial cells or monocytes take up and decompose and clear [10].
As early as the 1960s, Dr. 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, 12].
In 1989, Neil E. Simister and Keith E. Mostov finally cloned the receptor that protects IgG antibodies, which is the neonatal Fc receptor (FcRn) [13].
After 20 to 30 years of research, the mechanism of FcRn protecting IgG antibodies has been basically clarified. Specifically, IgG antibodies in blood are taken up by endothelial cells or monocytes, and after entering cells, IgG antibodies bind to FcRn in acidic (at pH 6-6.5) endosomes (millimolar or nanomolar levels).
IgG antibodies that are 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 7.4), IgG antibodies are separated from FcRn, and IgG antibodies are re-released into the interstitial fluid or blood [14].
Theoretically, through the binding of FcRn to IgG, the balance of IgG in the body can be adjusted: when IgG exists in a large amount, the FcRn that binds to IgG tends to be saturated, and the IgG that cannot bind to FcRn will be degraded by lysosomes, and when the concentration of IgG When low, IgG binding to FcRn is preserved [14, 15]. This is why the average half-life of IgG antibodies can be as long as 23 days. Animal experiments have shown that FcRn deficiency can shorten the half-life of IgG in mice from 6-8 days to 1 day [15].
It can be said that cells expressing FcRn are actually regulators of IgG antibody levels. Although IgG antibody glycosylation, charge and isoelectric point (pI), target-mediated drug disposition (TMDD), and anti-drug antibody (ADA) also affect antibody metabolism, FcRn is the most critical and The most studied IgG antibody metabolic regulator [14].
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 FcRn.
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 pH 6. Improve the affinity of the modified IgG and FcRn, and ensure that the separation of the two under physiological pH conditions is not affected.
In vivo experiments of these mutants have shown that they can extend the terminal half-life of engineered therapeutic antibodies in cynomolgus and rhesus monkeys by 2-4 fold [14].
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 time.
It is very valuable for the treatment and prevention of diseases . Studies have shown that prolonging the half-life of antibodies makes their effects more durable [16-18].
Of all the Fc mutation types mentioned above, YTE is one of the most studied and widely used forms of mutation . For example, the respiratory syncytial virus (RSV) neutralizing antibody Nirsevimab (MEDI8897) has been YTE-engineered.
Preclinical studies have shown that the introduction of YTE mutations in the Fc segment of Nirsevimab increases the half-life in cynomolgus monkeys by more than 3-fold compared with the original antibody [19].
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 [7].
Most importantly, the YTE-engineered antibody in the Fc segment can provide durable and effective protection .
For example, a single injection of nirsevimab reduces the risk of RSV infection in preterm/term infants seeking medical attention by more than 70 percent, and this protection lasts for at least 150 days [20, 21].
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 transformation .
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 [22].
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 extent. Resistance of mutants .
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 time. risk of infection .
In addition, the long half-life also provides the basis for clinical studies (in progress) of this combination post-exposure and pre-exposure prophylaxis.
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 90. days or so [24].
On the 20th of last month, a research team led by Mark T. Esser published detailed clinical data of the neutralizing antibody combination Tixagevimab/Cilgavimab for pre-exposure prevention of COVID-19 pneumonia in the New England Journal of Medicine [23].
First look at the demographic characteristics of the subjects enrolled in this study [23]: their mean age was 53.5 years, and 43.4% of the subjects were 60 years or older; 77.5% of the subjects were It is believed that there is a higher risk of severe illness after infection with the COVID-19.
The results showed that compared with placebo , the Tixagevimab/Cilgavimab combination reduced the risk of symptomatic infection of the COVID-19 by 82.8% at 6 months of follow-up [23]. This means that a single injection of the Tixagevimab/Cilgavimab combination can provide at least 6 months of immune protection in high-risk groups [23].
It is based on the above data that Tixagevimab/Cilgavimab has been approved by the FDA and EMA for pre-exposure prophylaxis against COVID-19 [25,26]. 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 COVID-19 vaccine due to immunosuppressive drugs or treatment; A history of adverse reactions, such as severe allergic reactions, is not recommended for anyone with an approved or licensed COVID-19 vaccine [25].
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 infection.
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 vaccines.
References: How long-acting neutralizing antibodies can achieve lasting protection against COVID-19?
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[9]. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493-507. doi:10.2165/11531280-000000000-00000
[10].Mould DR, Sweeney KR. The pharmacokinetics and pharmacodynamics of monoclonal antibodies–mechanistic modeling applied to drug development. Curr Opin Drug Discov Devel. 2007;10(1):84-96.
[11].BRAMBELL FW, HEMMINGS WA, MORRIS IG. A THEORETICAL MODEL OF GAMMA-GLOBULIN CATABOLISM. Nature. 1964;203:1352-1354. doi:10.1038/2031352a0
[12]. Brambell FW. The transmission of immunity from mother to young and the catabolism of immunoglobulins. Lancet. 1966;2(7473):1087-1093. doi:10.1016/s0140-6736(66)92190-8
[13]. Simister NE, Mostov KE. An Fc receptor structurally related to MHC class I antigens. Nature. 1989;337(6203):184-187. doi:10.1038/337184a0
[14]. Liu L. Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins. Protein Cell. 2018;9(1):15-32. doi:10.1007/s13238-017-0408-4
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[16]. Robbie GJ, Criste R, Dall’acqua WF, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. 2013;57( 12): 6147-6153. doi: 10.1128/AAC.01285-13
[17]. Griffin MP, Khan AA, Esser MT, et al. Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults. Antimicrob Agents Chemother. 2017;61(3):e01714-16. Published 2017 Feb 23. doi:10.1128/AAC.01714-16
[18]. Domachowske JB, Khan AA, Esser MT, et al. Safety, Tolerability and Pharmacokinetics of MEDI8897, an Extended Half-life Single-dose Respiratory Syncytial Virus Prefusion F-targeting Monoclonal Antibody Administered as a Single Dose to Healthy Preterm Infants . Pediatr Infect Dis J. 2018;37(9):886-892. doi:10.1097/INF.0000000000001916
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[24]. Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19. N Engl J Med. 2022;10.1056/NEJMoa2116620. doi:10.1056/NEJMoa2116620
[25]. https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-revisions-evusheld-dosing
[26]. https://www.ema.europa.eu/en/news/ema-recommends-authorisation-covid-19-medicine-evusheld
How long-acting neutralizing antibodies can achieve lasting protection against COVID-19?
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