Greiff, a professor at the Department of Immunology and Transfusion Medicine, Institute of Clinical Medicine, University of Oslo, has been awarded funding for the project EPIC-AB: Epistatic Principles for Immunoengineering of Antibodies.
The project will investigate how combinations of small genetic changes affect an antibody’s ability to recognise and bind to its target. The aim is to make the development of antibody-based medicines more predictable and targeted.
What are antibodies?
Antibodies are an important part of the immune system. They are proteins used by the body to recognise foreign invaders, such as viruses and bacteria, and can bind very specifically to particular targets.
This precision also makes antibodies valuable as medicines. Antibody-based therapies are already used in a wide range of modern treatments, including for cancer, autoimmune diseases and infections.
However, antibodies identified at an early stage are rarely ideal and often need further development before they can be used as medicines.
Mutations can interact
Researchers can improve antibodies by introducing small changes, known as mutations. These changes may strengthen and sharpen an antibody’s binding to its target, improve its stability, or help it remain effective when the target changes, for instance, when a virus mutates.
The challenge is that mutations do not always act independently.
“The effect of one mutation can depend strongly on which other mutations are present. A mutation that is harmful on its own can become beneficial when combined with another mutation,” Greiff explains.
This phenomenon is known as epistasis.
“It makes it difficult to predict which combinations of changes will produce a better antibody. As a result, antibody development still relies heavily on testing very large numbers of variants,” he says.
Searching for patterns in millions of variants
Greiff and his colleagues will use unique large-scale datasets containing millions of combinations of antibody and antigen variants. Antigens are the molecules that antibodies recognise and bind to.
The researchers will analyse these data to identify the underlying rules governing how mutations interact. They will then test whether these rules can be used to design improved antibodies.
“We want to understand whether there are patterns that can help us predict which changes will work well together,” says Greiff.
In the longer term, this knowledge could make it easier to develop antibodies that are more effective, stable and robust when their targets change. This could, in turn, lead to improved antibody medicines.
Basic research with major potential
The project is basic research and reflects the type of researcher-led, curiosity-driven work supported by FRIPRO.
“We want to discover previously unknown principles governing how antibodies recognise their targets,” Greiff says. “At the same time, the project is ambitious and involves some risk, because we do not yet know whether general rules of epistasis exist across different antibodies.”
He believes that FRIPRO is particularly well suited to this kind of research.
“Answering a fundamental scientific question could also open up new opportunities in antibody engineering and biotechnology,” he says.
Deputy Head of the Institute of Clinical Medicine, Shuo-Wang Qiao, welcomes the FRIPRO grant and highlights the importance of the research:
“We congratulate Victor Greiff on receiving the FRIPRO grant. Finding antibodies that bind to the right target can be a time-consuming process—often like looking for a needle in a haystack. Greiff’s research may help make this work more precise and efficient by predicting what an antibody recognises based on its unique sequence. In the long term, this could accelerate the development of new antibody-based medicines,” Qiao says.
Greiff is also the recipient of an ERC Consolidator Grant from the European Research Council.