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Several antibody drugs are ineffective against Omicron variants! Is there still a market for COVID-19 neutralizing antibodies?
Recently, GlaxoSmithKline (GSK) and its partner VIR Biotechnology jointly announced that the US FDA has revised the Emergency Use Authorization (EUA) Fact Sheet for the monoclonal antibody .
The FDA has determined that, based on all available evidence, including new live virus data generated by VIR, the 500 mg dose of Sotrovimab is unlikely to be effective against the Omicron BA.2 variant.
Based on this, GlaxoSmithKline and VIR are currently preparing a set of data to support higher doses of Sotrovimab for the Omicron BA.2 variant and will share these data with regulatory and medical authorities around the world for discussion .
In May 2021, the FDA granted Sotrovimab EUA: as a single-dose intravenous (IV, 500 mg) therapy for a positive direct SARS-CoV-2 virus test with a high risk of developing severe COVID-19 ( Adult and pediatric (age ≥12 years, weight ≥40 kg) patients including hospitalization or death) for the treatment of mild to moderate COVID-19.
Many people didn’t foresee that GSK’s neutralizing antibody also “lost” in the battle with Omicron. Before that, many industry insiders believed that GSK’s neutralizing antibody was one of the most promising products.
So, when most of the currently approved neutralizing antibody drugs are ineffective against the Omicron strain, is there still a market for the COVID-19 neutralizing antibody drugs?
Neutralizing antibody failed against OMICRON
According to GSK official information, Sotrovimab is an experimental SARS-CoV-2 neutralizing monoclonal antibody. The antibody binds to the same epitope on SARS-CoV-1 (the virus that causes SARS) and SARS-CoV-2, suggesting that the epitope is highly conserved and may make resistance difficult to develop.
Sotrovimab, developed using Xencor’s XtendTM technology, aggregates in the lungs, ensuring ideal penetration into SARS-CoV-2-infected airway tissue and extending half-life.
Previously, GSK and VIR released updated bioRxiv data saying that preclinical data showed that the investigational monoclonal antibody Sotrovimab has a key mutation in the new SARS-CoV-2 variant (B.1.1.529) Omicron 1 activity, including mutations found at the Sotrovimab binding site 1.
The data are based on pseudovirus testing of specific individual mutations found in Omicron. To date, Sotrovimab has demonstrated sustained activity against all detected variants of interest as defined by the World Health Organization.
In addition to the neutralizing antibody drug GSK, according to the Antibody Therapeutics database statistics, as of now, there are hundreds of neutralizing antibody projects targeting the S protein of the new coronavirus in the world, of which at least 20 projects have entered the clinical research stage.
At present, the products with fast clinical progress of neutralizing antibodies in the world are mainly Regeneron REGEN-COV2, Junshi/Lilly cocktail therapy Bamlanivimab+Etesevimab and AstraZeneca Evusheld. Among them, Regeneron REGEN-COV2 is the first U.S. EUA and Covid-19 neutralizing antibody cocktail therapy marketed in Japan.
Lilly’s cocktail therapy Bamlanivimab+Etesevimab is approved for a wide range of use globally, and AstraZeneca’s Evusheld is approved in the United States, the United Kingdom, and the European Union. As for single-use neutralizing antibody therapy,
it is mainly based on Sotrovimab developed by GSK and VIR, which can specifically recognize the conserved epitopes of the new coronavirus and reduce the possibility of virus mutants escaping.
However, due to the raging COVID-19 epidemic and the continuous mutation of the virus, among the several drugs that have been on the market, Roche & Regeneron’s REGEN-COV (casirivimab+imdevimab) and Eli Lilly’s Bamlanvimab+etesevimab are ineffective against Omicron mutants , therefore on January 24, 2022, the FDA revised its emergency use rights for these two COVID-19 neutralizing antibodies, limiting their use in the United States and limiting the use of these antibodies to those infected or exposed to those susceptible to these treatments. Patients with new coronavirus variants.
In this regard, some industry insiders analyzed the 21st Century Business Herald that neutralizing antibody drugs mainly inhibit the invasion of viruses by blocking the binding of the spike protein to its receptor ACE2 or blocking the conformational change of the spike protein.
The Omicron mutants have a large number of mutations in the viral spike protein. Based on the published literature and the structure of the new coronavirus S protein and different neutralizing antibodies, some of these mutations may affect the therapeutic effect of a considerable number of neutralizing antibody drugs, but the specific impact of an antibody needs to be determined by Experiment to verify.
Earlier, Regeneron also said that preliminary tests found that its new coronavirus antibody mixture drug was ineffective against the new strain of Omicron. This is an indication that some products of an important therapy may need to be modified if the new strain spreads widely.
Regarding the clinical therapeutic effect of neutralizing antibody drugs, Professor Lu Mengji of the Institute of Virology, University of Essen, Germany, said in an interview with the media that the effect of neutralizing antibodies on virus mutants is limited.
The virus will continue to evolve, and there will always be a stage when the neutralization efficiency of antibodies will drop to a certain extent.
Then its protective power and therapeutic effect will be greatly affected, and it will not have advantages in clinical treatment.
“The broad-spectrum antiviral drugs we are talking about now are aimed at a certain type of similar virus. However, the new coronavirus has specific diversity and evolution is not directional. Ending the epidemic may not be achieved through broad-spectrum drugs. A better way is to have Targeted and powerful drugs,” Lu Mengji said.
Are there still market prospects for neutralizing antibodies?
Neutralizing antibodies can effectively block the entry of the new coronavirus into human cells and are an effective means of treating COVID-19 pneumonia.
Neutralizing antibody therapy includes cocktail therapy and monotherapy. One or two antibodies bind to the viral RBD site to prevent the virus from entering cells.
In response to the impact of mutant strains, the use of cocktail therapy or single-use antibody therapy that recognizes conserved sites can reduce the possibility of mutant viruses evading antibody binding and improve the success rate of neutralizing antibodies in the treatment of COVID-19 pneumonia.
The barriers and challenges that neutralizing antibody companies are currently facing are mainly in three aspects:
- First, virus mutation may affect the neutralizing activity of neutralizing antibodies;
- The second is the inability to carry out large-scale coverage at the global level and become a universal drug;
- Third, the production requirements and costs of antibody drugs are relatively high, and the portability of transportation and use is subject to certain inherent limitations.
Although the field of neutralizing antibodies is controversial, neutralizing antibodies have both preventive and therapeutic effects. Compared with vaccines, neutralizing antibodies can be used not only for the treatment of patients infected with the new coronavirus, but also for preventive therapy, providing passive immunity to susceptible populations.
At the same time, neutralizing antibodies have a fast onset of action and can take effect immediately after receiving the injection, but they are also effective and specific for patients who cannot produce sufficient immune responses to the vaccine (such as the elderly and patients with suppressed immune systems). biological missiles”.
Monoclonal antibodies with neutralizing activity have the advantages of good specificity, high safety, clear mechanism of action, easy large-scale production, and can be used for both prevention and treatment. positive effect.
As for how to solve the above-mentioned barriers and challenges, it has become an important problem faced by companies in the development of neutralizing antibodies? This barrier can be broken through the unique Feitai antibody precision screening platform.
Specifically, the competitive screening is carried out by adding hAce2 and S1RBD proteins to the liquid phase. It is speculated that the neutralizing antibodies screened can simulate the spatial conformation of the receptor ACE2 to a certain extent, and have great potential for broad-spectrum neutralization of 2019-nCoV.
In addition, although many neutralizing antibodies “failed” in the battle with Omicron, it did not affect the market performance of enterprises in this field.
For example, on March 29, AstraZeneca announced that Evusheld (tixagevimab in combination with cilgavimab and cilgavimab), as a long-acting antibody combination, has been approved in the EU for use in adults and adults. Novel coronavirus pre-exposure prophylaxis in a broad population of adolescents (age 12 years and older and weighing 40 kg and over).
The recommended dose of Evusheld in Europe is 150 mg of tixagevimab tesagvirumab + 150 mg of cilgavimab sigavirumab, administered separately and consecutively intramuscularly.
The EU approval of Evusheld is primarily based on the results obtained from the clinical development program.
The preliminary analysis of the trial showed that compared with placebo, subjects using Evusheld had a 77% reduction in the relative risk of symptomatic COVID-19 infection; the median follow-up analysis of 6 months showed that the relative risk of symptomatic COVID-19 infection was reduced by 83% %; protection lasts at least 6 months.
Evusheld was well tolerated in clinical trials.
Several antibody drugs are ineffective against Omicron variants!
(source:internet, reference only)