Research into the current antibody-based drugs for COVID treatment shows that they need to be designed to work in concert with immune cells to be effective.
Three drugs using monoclonal antibodies are approved by the FDA to treat COVID, which provide the patient’s body with ready-made antibodies faster than can be produced by their own immune systems.
The distinctive Y shape of antibodies comes from their two short arms, which latch on to foreign molecules to clear them out, and a long effector arm which interacts with immune cells, inducing them to attack infected cells and release molecules that modulate the immune response.
In antibody-dependent enhancement, the long arm of antibodies can interfere with immune cells, such as in tropical dengue fever. Immunity against one strain against dengue fever causes life-threatening illness if infected with the other strain.
To investigate the possibility of this in COVID, some companies altered the long arm of their antibodies to prevent interaction with immune cells. Other companies took the opposite approach and strengthened antibody effector functions to boost the potency of their drugs.
“Some of the companies removed the effector functions from their antibodies, and other companies are trying to optimise the effector functions,” said senior author Michael S Diamond, MD, PhD, the Herbert S Gasser Professor of Medicine. “Neither of these strategies is backed by data in the context of SARS-CoV-2 infections. Based on our findings, if you have a potently neutralising antibody without effector functions and you give it before infection, as a preventive, it will probably work. But if you give it after infection, it won’t work well; you need to optimise effector functions to get maximal benefit.”
“‘Effector functions’ refers to a complex set of interactions between antibodies and other elements of the immune system,” said Prof Diamond, who also is a professor of molecular microbiology and of pathology and immunology. “You can introduce different point mutations to augment certain kinds of effector functions, and some might be harmful to the immune response while others might be beneficial. There’s a lot of nuance. We are still learning how to harness effector functions so you get what you want but not what you don’t want.”
To find how antibody effectors work with COVID, the researchers took an antibody which was known to be effective against the virus and disabled the effector so it could not interact with immune cells.
They administered the original antibodies, the disabled antibodies and placebo antibodies each to a different group of mice, which were infected a day later with SARS-CoV-2. Both normal and disabled effector antibodies were able to protect against the disease. There were no signs of antibody enhancement of the disease, fortunately.
To find out whether the effector function was needed for treatment after infection, they infected mice with SARS-CoV-2 and administered one of the three sets of antibodies to mice one, two or three days later. Only the original antibodies protected the mice from the disease. The tests were run in hamsters with the same results.
The researchers discovered in the study that losing effector functions changed the types of immune cells recruited to fight the COVID infection and the way they behaved.
Source: Medical Xpress
Journal information: Emma S. Winkler et al, Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection, Cell (2021). DOI: 10.1016/j.cell.2021.02.026
