Antibody ‘Effector Function’ Important For COVID-19 Treatment Efficacy

Antibody ‘Effector Function’ Important For COVID-19 Treatment Efficacy
Illustration of antibodies (red and blue) responding to an infection with the new coronavirus SARS-CoV-2 (purple). The virus emerged in Wuhan, China, in December 2019, and causes a mild respiratory illness (covid-19) that can develop into pneumonia and be fatal in some cases. The coronaviruses take their name from their crown (corona) of surface proteins, which are used to attach and penetrate their host cells. Once inside the cells, the particles use the cells' machinery to make more copies of the virus. Antibodies bind to specific antigens, for instance viral proteins, marking them for destruction by other immune cells.

Research led by Washington University School of Medicine suggests that antibody therapies designed to treat the symptoms of severe COVID-19 need to be able to interact with the immune system via an ‘effector function’ to produce the best therapeutic result.

Since the beginning of the pandemic, researchers working to develop therapies for COVID-19 have realized the potential of antibody treatments both as a prophylaxis and treatment for the symptoms of severe disease.

Most antibodies have two short arms and one long arm. The short arms allow recognition of a huge range of different targets, such as a viral particle, whereas the long arms have an ‘effector function’ that allows them to interact with the immune system of the infected person. This effector function allows the antibody to summon immune cells in the body to help destroy infected cells and fight infections.

Developers of antibody-based therapeutics for COVID-19 have been cautious about leaving the effector function of antibodies intact. This is because for some viral infections, such as dengue virus, interactions between this part of the long arm of existing antibodies can actually result in a worse infection and symptoms if the person with the antibodies is exposed to the virus a second time.

The speed of the pandemic and size of the medical need has led to therapies being developed or tested quickly and often without in-depth knowledge of how they interact with the immune system.

“Some of the companies removed the effector functions from their antibodies, and other companies are trying to optimize the effector functions,” said Michael Diamond, M.D., Ph.D., a professor at Washington University School of Medicine. “Neither of these strategies is backed by data in the context of SARS-CoV-2 infections.”

To try and combat this, a research team led by Diamond carried out an animal study to test what impact the antibody effector functions had on efficacy of antibody therapy given both as prophylaxis and treatment for infection with SARS-CoV-2.

As reported in the journal Cell, the team modified several anti-COVID-19 antibodies, discovered in summer 2020, to create a treatment without an effector function and a version with this function intact. They then tested the impact of these antibodies as both a prophylaxis against later infection and a treatment to combat current infection in a mouse and hamster model.

While the effector function did not seem to impact the efficacy of the antibodies for prophylactic purposes, the antibodies with intact effector function were better at treating symptoms of current infection than those without this capacity.

“Based on our findings, if you have a potently neutralizing 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 optimize effector functions to get maximal benefit,” explained Diamond.

The team examined the physiological differences in the immune response to the different types of antibodies and found that antibodies with an intact effector function seemed to reduce inflammation and improve respiratory symptoms more than those without this function.

“‘Effector functions’ refers to a complex set of interactions between antibodies and other elements of the immune system,” said Diamond. “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.”

This study was carried out in an animal model, but gives some insight into when it might be important to keep the effector function intact when developing antibody treatments for COVID-19 or other similar infections. The researchers suggest more research into this finding is needed to confirm these results and validate them in human COVID-19 patients.