After these first months of trial and error, it seems that we have fewer pawns on the board. Resorting to survivor plasma is not the solution either, at least not as fast and effective as intended, due to difficulties and side effects.
However, antibodies, molecules custom designed by our immune system, can be manufactured in series. Will they be the queen of the board and put the viral crown in check?
The game begins
The first files were based on drug repositioning, one of the fastest and safest strategies for identifying drugs.
Different platforms, such as Solidaridad or REMAP-CAP, were created to test the efficacy of these well-known drugs (Table 1). Innovative methods were used, simultaneously testing multiple combinations of potential therapies, unlike traditional trials, in which only one drug is studied in a much slower process.
The negative results of the Solidarity trial have recently been confirmed. Trials of the four treatments evaluated (remdesivir, hydroxychloroquine, lopinavir / ritonavir, and interferon) have shown little or no effects, both in terms of overall mortality, as well as in the time elapsed until the initiation of mechanical respiration or the duration of hospitalization. in admitted patients.
In addition to antivirals and anti-inflammatories, other compounds have been studied, such as vitamin C and colchicine. Unfortunately, as we see in the table, the results of the trials have not been very encouraging.
Nor is the plasma treatment of survivors, which emerged as the first rapid and affordable therapy, is valid. The risks involved have ruled out its use.
Monoclonal antibodies, the definitive therapy?
But we still have chips on the board to fight back. Of the 319 trials of compounds currently against COVID-19, 80 studies correspond to antibodies as therapeutic agents. About a dozen are already in phase III, and as many in phase II. This means that they are very close to their final approval.
Antibodies (also known as immunoglobulins) are Y-shaped proteins (figure 1) that float in the blood and are capable of sticking (binding with high affinity) to a protein from a bacterium or virus (called an antigen). The pathogen is thus deactivated or marked so that the rest of the immune system can detect and destroy it.
Antibodies are secreted by so-called plasma B cells, which appear in the blood when an infection begins. Each antibody is specific for an antigen. Much of the structure is common to all of them, but there are small areas at the upper ends of the Y, called variable regions, which are distinct and specifically recognize various pathogens.
This great diversity of antibody-producing cells appears in humans during childhood development, as a consequence of random combinations and subsequent mutations in the genes that encode these variable regions. In this way, when the human being reaches adolescence, he already has in his body a baggage of B cells capable of producing antibodies against a myriad of possible infections.
How are they produced outside of our body?
The design of antibodies to act against specific targets in diseases and infections began in 1975 with the work of Khöler and Milstein. These researchers fused mouse cells and cells of unlimited growth (from tumors) to fine-tune the hybridomas, a result for which they received the Nobel Prize in 1984.
Monoclonal antibodies, highly specific and produced in an unlimited way, are purified and used therapeutically (figure 2).
The first therapeutic monoclonal antibody, muromonab, was developed for transplant rejection and was approved in 1986. But due to its non-human origin, it had adverse effects.
Thanks to genetic engineering techniques, monoclonal antibodies have been progressively modified so that they increasingly resemble human antibodies, avoiding immunological problems (Figure 3).
Currently, starting on a small scale from the elaboration in laboratory cultures, they are produced on a large scale and transformed for their subsequent formulation and administration (figure 4).
The first monoclonal antibody approved for use against COVID-19 was bamlanivimab, conditionally authorized in the US since the safety and efficacy data have not yet been verified by the scientific community. Regulatory authorities decided to approve it in advance due to the emergency situation, with the commitment that these data must be made public in a short time.
Finally, it should be noted that the capacity of the antibodies is not only therapeutic. They can also be used as prophylaxis by passive vaccination. It has recently been shown that, even if the immunity provided was not long-lasting, it would protect against contagion. This double action could give the antibodies, in addition to a hope, the role of queen on the board.
We do not yet know the outcome of the game, but in the current circumstances, a treatment, if effective, means a lot. The final checkmate is closer.
María Mercedes Jiménez Sarmiento, CSIC Scientist. Systems Biochemistry of the bacterial division. Scientific communicator, Margarita Salas Biological Research Center (CIB – CSIC); Matilde Cañelles López, Scientific Researcher. Science, Technology and Society and Nuria Eugenia Campillo, Senior Scientist. Medicinal Chemistry, Margarita Salas Biological Research Center (CIB – CSIC)
This article was originally published on The Conversation. Read the original.
