In-depth inventory-the development status of respiratory syncytial virus (RSV) antibodies

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, Price comparison, and order follow-up are all handed over to them, saving worry and money! Respiratory syncytial virus (RSV) infection is an important cause of acute lower respiratory tract infections in children under 5 years of age worldwide, and it is also one of the main causes of infant deaths
.

The hospitalization rate of RSV infection among children under 1 year old in the United States is 1.
1%, and the prevalence rate in developing countries is on the rise
.

PART01.
Virus structure and infection mechanism RSV belongs to Paramyxoviridae, Pneumoviridae; it is a non-segmental single-stranded parastrand RNA virus with a diameter of 80-150nm, a virus envelope and a spike
.

The full length of the genome is about 15Kb, containing 10 genes, encoding 11 proteins, including 8 structural proteins (F, G, M2-1, M2-2, SH, N, P, L) and 3 non-structural proteins (NS1 , NS2, NS3)
.

Among them, fusion protein (F) and attachment protein (G) are the two main envelope glycoproteins.
F is a typical type I glycoprotein.
After cleavage by cell protease into F1 and F2, it has biological characteristics.
Activity, can make the virus envelope fuse with the host cell membrane to form multinucleated giant cells.
G protein is a type II glycoprotein that can bind to the host cell membrane receptor and mediate the virus into the host cell
.

Compared with G protein, F protein has less variation and is relatively stable, so it is an important target for drug development
.

The F protein of RSV is a trimeric structure, which mediates the fusion of the virus envelope and host cells through drastic conformational changes
.

Before the fusion is initiated, the F protein adopts a pre-fusion conformation, which is unstable and has a lower energy barrier.
When it is very close to the host, the fusion peptide is inserted into the host cell membrane, and the F protein can cross the viral envelope and The host cell has two membranes
.

Subsequently, the F protein forms a trimer hairpin structure, which connects the two membranes together to promote fusion, and the conformation after fusion is very stable
.

The F protein trimer in the pre-fusion conformation is in the shape of a "lollipop", and the F protein in the post-fusion conformation is in the shape of a "crutch".
The two conformations are very different in structure and have different epitopes
.

Ideally, in order to prevent the entry of viruses, it is necessary to develop drugs with the epitope in the pre-fusion conformation of the F protein
.

  Fig.
1 Pre-fusion and post-fusion conformation of RSV F protein PART02.
Antibody development and clinical situation There are currently four antibodies targeting RSV: Pavilizumab (developed by MedImmune LLC and listed in 1998); MEDI8897 (alias nirsevimab, by MedImmune LLC) development, is currently in phase III clinical); MK-1654 (developed by Merck, is currently in phase III clinical); and domestic beadsdeclared IND five years in 2021, is currently in phase I clinical
.

Table 1 Summary of RSV listing and clinical stage antibodies As the only antibody currently on the market, Palivizumab is obtained through hybridoma screening and humanized transformation, retaining about 5% of the mouse anti-sequence
.

The antibody targets the site II epitope of the F protein.
Because the neutralizing activity of the antibody is low, the current indication is only used to prevent premature infants with congenital heart disease or lung disease for less than 35 weeks.
It is clinically comparable to placebo In comparison, the hospitalization rate of RSV infection in children with indications has been reduced by 55%
.

In 1998, Palivizumab was approved by the FDA for the first time.
In 2008, its sales reached more than 1 billion U.
S.
dollars, and its sales exceeded 1 billion U.
S.
dollars for 7 consecutive years.
It entered the blockbuster drug club. .

Among the antibodies currently under research, MEDI-8897 is a recombinant human IgG1κ monoclonal antibody being developed by AstraZeneca.
It is obtained through B cell sorting, which is a fully human antibody that targets the site 0 epitope of the F protein
.

It launched a large-scale clinical trial of 1453 people in 24 countries in Phase II.
The antibody significantly reduced the number of cases of lower respiratory tract infection caused by RSV during the entire RSV epidemic season, and reduced the hospitalization rate of RSV infection in premature infants.
The Fc region has been modified by YTE to extend the half-life, allowing only one injection during the RSV epidemic season.
In terms of safety, the adverse events between MEDI8897 and placebo are similar.
Such solid data has made everyone very optimistic about it.
An important factor for the success of Phase III
.

In March 2017, AstraZeneca and Sanofi reached an agreement to develop and commercialize MEDI-8897
.

According to the terms of the agreement, AstraZeneca will lead all development activities and preliminary regulatory approvals, and retain production activities, and Sanofi will lead commercialization activities
.

Like MEDI-8897, MK-1654 is also a fully human antibody, and the Fc region has been modified with YTE to extend its half-life
.

The clinical data of MK-1654 is relatively small.
In addition to the clinical safety and pharmacokinetics of one item, perhaps due to clinical recruitment restrictions, the phase II effectiveness of MK-1654 adopts the strategy of RSV A virus for adult challenge.
67 people completed this clinical trial.
In view of the presence of RSV antibodies in adults, only one of the viruses was used in the clinic for challenge.
In addition, whether the antibody is effective against the site IV epitope of the F protein is still unconfirmed, so the phase III clinical trial The final result of the data remains to be seen
.

PART03.
Looking at the key elements of RSV clinical success from clinical failure antibodies.
Throughout the history of RSV antibody development, there are three main antibodies that have failed: Motavizumab (developed by MedImmune LLC); REGN2222 (alias Suptavumab, developed by Regeneron); ALX -0171 (Nanobody, developed by Ablynx NV)
.

Table 2 Summary of RSV failed antibodies Motavizumab is an upgraded product of Palivizumab, which is obtained by the affinity maturation of Palivizumab
.

However, due to the serious allergic reaction problem and the failure to show non-inferiority significantly better than Palivizumab, in June 2010, the FDA Antiviral Drug Advisory Committee voted 14 against and 3 votes in favor, and it is not recommended to approve Motavizumab
.

Compared with tumors and autoimmune disease antibodies, the neutralizing antibody mechanism of viruses is very simple, and the in vitro activity can often reflect the ultimate effectiveness
.

In vitro activity comparison is not difficult to see that the neutralizing activity of the virus is MEDI8897>REGN2222>Motavizumab>Palivizumab.
From the perspective of clinical effectiveness, MEDI8897, Motavizumab, and Palivizumab all show excellent clinical effectiveness
.

The failure of REGN2222 is due to the epitope.
The antibody targets the epitope of the RSV F protein Site V.
The 172 173 sites of the current epidemic strains have all been mutated, which directly leads to the ineffectiveness of the antibody
.

Table 3 Preclinical in vitro cell activity of RSV antibody Table 4 Clinical effectiveness of antibody ALX-0171 cannot be used for the prevention of RSV due to the half-life of the nanobody.
This is currently the only drug developed into a therapeutic antibody.
We will study it carefully Clinical data will find that ALX-0171 still shows better efficacy than placebo in reducing viral load, but there is no difference between the primary endpoint based on discharge time and the placebo group.
However, we study MEDI8897.
The data also found that even MEDI8897, which showed great clinical prevention effects, did not show superiority to the placebo group in the discharge time of children after hospitalization.
Therefore, how to set up the clinic is also one of the important factors for success.
That's why the clinical development of MEDI8897 and MK-1654 starts with premature infants who are more susceptible to infection, and then develops the clinical practice of healthy term infants, because the weaker the immune system, the easier it is to achieve clinical effectiveness
.

Table 4 Comparison of the discharge time of RSV patients after hospitalization.
In summary, for antiviral antibodies, excellent in vitro activity data, broad-spectrum virus neutralization activity, and prayer that the virus does not mutate at the key site of candidate antibody binding are often such The key elements for the successful clinical development of antibodies, of course, as drugs for children, especially infants and young children, low immunogenicity and safety have always been factors that cannot be ignored
.

PART04.
Summary With the continuous in-depth research on the structure and pathogenic mechanism of RSV virus, the development of RSV-specific treatments will also be more population-specific and diversified
.

At present, there is still a lack of cost-effective and specific treatment for RSV infection.
Palivizumab is currently the only antibody used to prevent RSV.
As a blockbuster product with annual sales of more than 1 billion US dollars, its indications are currently only for high-risk preterm births.
Children, this part of children only accounts for 2% of the total birth children, with the subsequent development of more potential drugs, this will surely be a broad market
.

As a viral preventive therapy, most of the competitors in the field of RSV new drug development come from vaccines
.

The current potential challenge may come from the vaccines independently developed by GlaxoSmithKline and Pfizer.
Both vaccines are in the key III trial stage.
However, the current clinical strategies for child prevention are all maternal immunization strategies, and the effectiveness of the vaccine still needs Based on the final clinical data, if clinically successful, it will become a strong market competitor for antibodies
.

Of course, antibodies and vaccine products are not incompatible between water and fire.
Clinically, the differences in different treatment methods should be considered to ensure that patients can get the best prevention and treatment in different situations
.

 References[1] Jason S.
McLellan, et al.
Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody[J].
Science, 2013, 340(6136):1113-1117.
[2] Griffin MP, Yuan Y, Takas T, et al.
Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants[J].
New England Journal of Medicine, 2020, 383(5):415-425.
[3] Tang A, Chen Z, Cox KS, et al.
A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein[J].
Nature Communications, 2019, 10(1):1-13.
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