What is the COVID-19 antibody drug? How does it work?

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What is the COVID-19 antibody drug? How does it work?

What is the COVID-19 antibody drug? How does it work? Is it a vaccine substitute hyped by some people?

1. What is the COVID-19 antibody drug

Monoclonal antibodies, cocktail antibody therapy, COVID-19 antibody drugs, these words often appear in media reports, and there are also some unnecessary controversies, such as being hyped by some people in the United States as vaccine substitutes. First explain what an antibody drug is.

COVID-19 antibody drugs are all monoclonal antibodies. Antibodies have been heard many times since the epidemic. Antibody is a protein secreted by B cells in the body’s immune system.

It can bind to a certain antigen very specifically. For example, after the human body is infected with the COVID-19 virus, it can produce antibodies against some proteins on the COVID-19 virus, and these antibodies will bind to these proteins very specifically.

The proteins on the new coronavirus are antigens. For the same antigen, such as spike protein, the human immune system can produce many different antibodies, which bind to different positions on the spike protein.

This diverse antibody response is called polyclonal. The monoclonal counterpart is a specific antibody molecule.

This is to discuss antibodies from the perspective of human immune response, and also to make some basic definitions of antibodies. In terms of function, especially from the perspective of anti-virus, some antibodies can prevent the virus from infecting cells due to the special binding position after binding to the virus.

For example, another term we often hear about antibodies-neutralizing antibodies, is to describe antibodies from the perspective of preventing viruses from infecting cells. Antibodies with such functions can naturally associate with antiviral medical effects.

This is indeed the case. For example, a method of treating the COVID-19, plasma therapy, actually uses antibodies against the COVID-19 in the survivor’s serum to prevent the virus from spreading in the infected person’s body and play a therapeutic role.

Combining the previous definition of antibodies, it is not difficult to find that plasma therapy can be said to be using polyclonal antibodies. Let’s diverge our thinking. Antibodies are a kind of protein, and now it is possible to produce proteins in large quantities for use as medicines.

For example, insulin is a kind of protein, and the insulin used for type 1 diabetic patients is artificially produced. Antibodies can also be produced as medicines like medical insulin.

However, the antibodies produced as drugs are all monoclonal. That is, only one antibody molecule is selected for mass production. This makes sense. Taking the COVID-19 as an example, when developing and producing antibody drugs against the COVID-19, we can choose the antibody molecule with the strongest binding ability to the COVID-19 virus and the highest antiviral efficiency.

For each monoclonal antibody, its binding antigen position is unique. Take the COVID-19 monoclonal antibody drugs as an example. These are antibodies against the spike protein, a monoclonal antibody that binds to a specific location on the spike protein.

At this time, it is necessary to consider that the virus will mutate. A single monoclonal antibody can achieve strong binding ability and bring strong anti-virus ability, but it may happen to encounter a mutation that affects the position where it binds to the virus. Lead to a decline in antiviral ability.

Therefore, many COVID-19 antibody drugs are used in combination with two different monoclonal antibody drugs. Sometimes reported that cocktail therapy refers to this situation in which two monoclonal antibody drugs are used together.

The above are some background introductions to antibody drugs. After reading this part, it is estimated that you will understand the meaning of related terms mentioned in media reports.

The following are specific COVID-19 antibody drugs. There are three types of COVID-19 antibody drugs used on a large scale:

One is Eli Lilly’s antibody drug, which is a combination of two monoclonal antibodies, one of which is bought from a Canadian biotech company, and the other is bought from a Chinese pharmaceutical company Junshi. So sometimes when I see Eli Lilly’s antibodies, I will mention these two companies.
The other is Regeneron’s antibody drug, which is also a combination of two monoclonal antibodies. These two were made by Regeneron itself.

The last one is a collaboration between Vir and GlaxoSmithKline (GSK), just a monoclonal antibody. Why does it use one instead of a combination of two? Because it was screened from the library of antibodies against SARS.

It can be combined with SARS, and it can be inferred that the position where it binds is very conservative for the coronavirus, and mutations are unlikely to occur.

Therefore, the two companies feel that their antibodies are unlikely to be affected by virus mutations and only use one antibody.

These antibody drugs are similar in the mechanism of action, that is, as mentioned earlier, they bind to the virus very efficiently and prevent the virus from entering the cell.

Therefore, when using it, it should be in the early stage of infection, which can prevent or slow down the speed of virus expansion in the body, and then shorten the patient’s recovery time and reduce the risk of severe illness.

2. What is the effect of the COVID-19 antibody drug?

There has been a lot of controversy recently on the role of monoclonal antibodies. Some people have exaggerated the scope and effect of these drugs for various purposes.

Based on the results of a clinical trial published in the New England Journal of Medicine for the monoclonal antibody drugs of Regeneron two days ago, we will talk about the applicable population and effects of this type of drug.

This is a paper formally published on September 29 and is the result of a Phase III clinical trial. The population it selects is outpatient, outpatient.

These patients are not hospitalized. A very important distinction between COVID-19 antiviral drugs is whether they are for outpatients or inpatients.

For example, Remdesivir is an inpatient. It has recently succeeded in an outpatient trial, but it is unlikely to be used on a large scale because it is a continuous intravenous injection of the drug for 5 days and outpatient clinics are not realistic.

Anti-viral monoclonal antibody drugs are generally used in the early stage, and one intravenous injection is the entire course of treatment, so it is more suitable for outpatients.

This clinical trial of Regeneron enrolled 3088 patients. The recruitment criteria are within 72 hours of a positive nucleic acid test and within 7 days of the onset of symptoms.

This ensures that it is an early patient. Then at first it recruited the patient regardless of the risk of severe illness, but later changed it to require at least one factor that increases the risk of severe illness, such as underlying diseases.

Why is this change? Because the end point of clinical trials is to see whether the risk of developing severe illness can be reduced. Therefore, it is necessary to concentrate on recruiting those who have a higher risk of severe illness after infection, so that it is easy to have enough severely ill people to judge whether the drug is effective.

The enrolled patients will be randomly assigned to inject different doses of antibody drugs or placebos, and follow up for 29 days to see the recovery time, whether they need to be hospitalized, or most unfortunately, death.

Different doses of antibody drugs are tested separately, so there are different placebo groups corresponding to each other. From the results, 1355 people used 2400 mg of antibody medicine, 2400 is the total dose, which is equivalent to 1200 for each of two monoclonal antibodies.

Among them, 18 people were hospitalized or died, which is 1.8%. Corresponding to 1341 placebo patients, 62 were hospitalized or died, the ratio was 4.6%. In contrast, antibody drugs reduced the risk of hospitalization or death by 71.3%.

Another low-dose group was 1200 mg. Seven of the 736 patients in the drug group had hospitalizations or deaths, the ratio was 1%, and 24 of the 748 patients in the placebo group, the ratio was 3.2%, and the relative risk was reduced by 70.4%. . It can be seen that both doses can effectively reduce the risk of patients developing severe illness or death. But it is not 100% effective.

Then if you look at the recovery time, that is, the time for the symptoms to disappear, compared with the placebo group, the average recovery time is 14 days. The recovery time for the two different doses is 10 days, which is 4 days shorter. From the point of view of the drug load from before the drug to 7 days after the drug, the antibody drug also accelerated the decline of the drug load.

From these results, it can be seen that antibody drugs are indeed very effective. After use, they can greatly reduce the risk of hospitalization and shorten the recovery time. But the premise is to use it early.

Some studies have shown that for some hospitalized patients, that is, patients who are already severely ill, if they do not produce antibodies themselves, antibody drugs will have a certain effect.

But for the vast majority of patients, if they are already severely ill, antibody drugs will not help much. This is determined by the mechanism of this type of drug. It works by slowing down the spread of virus amplification, so it must be used before the peak of virus replication. After the peak of replication, the effect is limited.

Antibody drugs are now mainly used as a treatment for people who are infected with the COVID-19 and are at a higher risk of severe illness. However, the half-life of antibodies in the body is relatively longer, which can also be used for prevention.

That is, to inject people who are not infected to reduce the risk of infection. This is mainly for people with immunodeficiency. These people may not have a good immune response after being vaccinated. Preventive injection of antibodies can play a protective role. But this is not like a vaccine that can provide long-term protection.

The injected antibodies have to be re-injected after they are metabolized in the body. The half-life observed in the Phase III clinical trial of Regeneron, an antibody drug, is more than 20 days. Now AstraZeneca has an antibody drug with a half-life that can reach half a year, but that one has just completed clinical trials and has not been on the market.

Preventive use of antibodies will only be a very small number of people, after all, this is a temporary means, not as effective as vaccines in prevention. In addition, the output of antibody drugs is limited. Both 1200 mg and 2400 mg are very large quantities. The supply of these drugs is limited.

The cost is also very high, and now it is basically government procurement. Although the patients do not need to pay, the purchase price should be more than US$1,000. It is absurd to promote antibody drugs as being able to replace vaccines.

Reference:
Regenerant antibody drug clinical trial results: https://www.nejm.org/doi/full/10.1056/NEJMoa2108163?query=featured_home