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New findings involving effector functions of antibodies could help improve the design of next-generation anti-COVID-19 drugs.
Researchers at the Washington University School of Medicine in St. Louis (St. Louis, MO, USA) have found that the ability to interact with other parts of the immune system is an essential component of effectiveness. antibodies. The findings could help improve the design of the next generation of antibody-based COVID-19 drugs.
Of the nine treatments and preventatives for COVID-19 approved for emergency use by the FDA, three are drugs based on so-called monoclonal antibodies. These drugs provide patients with ready-to-use antibodies that neutralize the virus, bypassing the body’s slower and sometimes less efficient process of making its own antibodies. But such therapies have been developed without detailed information on how antibodies interact with the rest of the immune system during COVID-19. Faced with a deadly and rapidly spreading new disease, drug designers began to work without knowing whether the ability of antibodies to activate a variety of immune cells would help or hinder efforts to control the disease. These abilities are collectively known as the effector functions of antibodies. The new study has shown that the effector functions of antibodies are a crucial part of the effective treatment of SARS-CoV-2 infections, but that they are unnecessary when antibodies are used to prevent infection. The findings could help scientists improve the next generation of antibody-based COVID-19 drugs.
The antibodies are shaped like the letter Y. The ends of the two short arms are almost infinitely changeable, giving the antibodies the ability to recognize virtually any molecular shape. The short arms attach themselves to foreign molecules and target them for clearance. The long arm is where the effector functions are located. It attaches to receptors in immune cells, causing them to kill infected cells and release molecules that shape the immune response. But this process can go wrong. In a process known as antibody-dependent boosting, interactions between the long arm of antibodies and immune cells can worsen some viral infections, including tropical dengue virus infections. People who have antibodies to one strain of dengue virus are at risk of developing life-threatening dengue if they are infected with another strain of the virus.
To avoid the danger of antibody-dependent improvement, some companies developing antibody-based COVID-19 drugs have altered the sequence in the long arm of the antibodies to prevent it from interacting with immune cells. Other companies have taken the opposite approach: strengthening the effector functions of antibodies to potentially increase the potency of their drugs. To determine the role of antibody effector functions in COVID-19, the researchers started with an antibody that was very effective at recognizing and neutralizing SARS-CoV-2. They eliminated the effector functions of the antibody by mutating its long arm so that it could not stimulate immune cells. The researchers gave separate groups of mice the original or mutated SARS-CoV-2 antibodies, or a placebo antibody that does not recognize SARS-CoV-2. The antibodies were given to the animals a day before they were infected through the nose with the virus that causes COVID-19. Regardless of whether the effector functions of the antibodies were intact, the anti-SARS-CoV-2 antibodies protected mice against the disease. The mice who received either of the anti-SARS-CoV-2 antibodies lost less weight and had lower levels of the virus in their lungs than those who received the placebo antibody. Importantly, there was no sign of an increase in antibody-dependent disease.
Next, the researchers investigated whether the effector functions of the antibodies were necessary for treatment after infection. They gave the mice the virus responsible for COVID-19 and treated them one, two or three days later with the original or mutated anti-SARS-CoV-2 antibodies, or a placebo antibody. Compared to placebo, the original anti-SARS-CoV-2 antibody protected mice against weight loss and death, but not those without effector functions. Further experiments with different antibodies with and without effector functions, and in a different animal – hamsters – gave the same result: effector functions are an essential part of effective antibody treatment against COVID-19. Some antibody-based drugs for COVID-19 are in development as a preventative measure for use in high-risk environments such as nursing homes. But most of these drugs are aimed at treating people who are already infected. To that end, optimizing the effector functions of antibodies could be the key to making a potent drug, the researchers say. In this study, the researchers found that the loss of effector functions altered the types of immune cells recruited to fight infection and their behavior.
“Some companies have removed effector functions from their antibodies, and other companies are trying to optimize effector functions,” said lead author Michael S. Diamond, MD, PhD, Herbert S. Gasser professor of medicine. “None of these strategies are supported by data in the context of SARS-CoV-2 infections. Based on our findings, if you have a strong neutralizing antibody with no effector functions and you give it before infection as a preventative measure, it will likely work. But if you give it after infection, it won’t work well; you need to optimize the effector functions to get maximum benefit. “
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Washington University School of Medicine in St. Louis
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