A team of scientists recently announced progress in the discovery of a pair of monoclonal antibodies that may be useful for the prevention and treatment of Covid-19. The work was described in the June 12th issue of Science Magazine.
The scientists began the process by isolating live antibody-producing cells from the blood of convalescent patients. They used a key fragment of the virus spike protein as bait to fish for cells that make the antibodies of interest. The bait fragment is the precise region of the spike protein that attaches to the ACE2 surface structure to begin the process of infection. The idea behind their choice was that antibodies that block the attachment of the virus to the cell will prevent infection altogether. Their fishing expedition was successful. They settled on four antibody-producing cells that met their criteria.
The next step was to isolate the genes (the bits of DNA in the cell) that specify each of the antibodies. Again, they were successful.
The next challenge was to develop each as a potential drug. To do so, they needed to insert the genes into a cell suitable for large scale production of the antibodies. This they also did.
The first test of the four antibodies was to determine whether the antibodies attached to the SARS-CoV-2 spike protein as expected. All passed this test. The virus that causes SARS-CoV-1 also uses the ACE2 protein as a receptor but none of the four antibodies attached to the SARS-1 spike protein.
The next question the researchers needed to answer was whether the antibodies blocked binding of the spike protein to the ACE2 receptor. Two of the four antibodies did and the other two did not. The team then focused their attention on the two ACE2-blocking antibodies.
Did both blocking antibodies bind to the same part of the spike protein? If they did, binding of one should interfere with binding by the other. What they found was the two antibodies did interfere with one another but only weakly, suggesting that they attach to overlapping but not identical regions of the spike.
To understand exactly how the antibodies block binding to the ACE2 receptor, the atom-to-atom contacts of one of the antibodies to the spike protein was determined by X-ray crystallography of the antibody-spike protein complex. The result: the antibody studied binds to 18 of the 21 ACE2 attachment sites. In other words, when the antibody binds to the spike protein it almost completely covers the ACE2 attachment site.
The next obvious question is, do the antibodies prevent infection? The hope is that if they do, two together should be more powerful than one alone. The experiments fulfilled that hope. Each of the antibodies on its own can neutralize the virus. The two together are more effective than either alone.
The final experiment was to determine if the antibody acted against SARS-CoV-2 in an infected animal. They chose mice for convenience even though SARS-CoV-2 does not usually kill those animals. The antibodies were introduced in the mice 12 hours after the viral challenge. The experiment showed that the antibody treatment reduced the amount of virus in the animals by 32.8% for one of the antibodies and 26% for the other, when compared to a control group three days post-infection. The animals treated with each antibody also had fewer lung lesions than the placebo control animals.
A next logical question, do the antibodies prevent infection of naive animals if not reported? It is likely that they will. Monoclonal antibodies used to treat respiratory syncytial virus protect very young children from infection. A monoclonal antibody that treats anthrax infections also prevents infection.
The work is a tour de force not only for the clarity and completeness of the results but also for the speed with which all the many steps were accomplished. The work reveals the stepwise question and answer process of successful scientific experiments each performed in a clear logical progression. The work also attests to the power of modern bioscience as each of the steps is, in itself, demanding technical exercise.
Apart from elegant science, the work offers hope that combinations of monoclonal antibodies can be used to treat and to prevent Covid-19. As an aside, combinations of antiviral drugs often work better than drugs used alone as coronaviruses, like many other viruses, are known to develop resistance to single drugs.
As a treatment, it is likely that combinations of monoclonal antibodies can prevent those infected from becoming ill, and if used early enough, may prevent those who are seriously ill from dying.
Used as prophylactics, such antibodies may protect healthcare workers. They may also be used to prevent those exposed at home or in the workplace, and perhaps even those identified as exposed by contract tracing. One happy way to describe such a success is that monoclonal antibodies may be the equivalent of a short-acting vaccine.
For now, all such good news must await human trials. The experiments described here demonstrate that success is in reach, not only for the effort of this group, but for many others who are on the same trail.