Activating the complement immune system to boost anticancer therapy

Disease and treatment 14. sep 2023 3 min CSO Nick Laursen Written by Kristian Sjøgren

I kampen mod kræft vil forskere gerne aktivere så meget af kroppens eget immunforsvar som muligt. Nu viser forskere, at man med bispecifikke antistoffer meget effektivt kan rekruttere en hidtil underudnyttet del af immunforsvaret i angrebet mod kræftcellerne.

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Researchers want to activate as much of the immune system as possible to combat cancer. Now they have shown that bispecific antibodies can very effectively activate the underexploited complement part of the immune system to kill cancer cells.

Combatting cancer requires more than one tool, and doctors worldwide are trying to defeat cancer by attacking it from many angles, both internally and externally.

Now a new study shows that bispecific antibodies can be used to potently activate the complement system, a previously underexplored part of the immune system, to kill cancer cells.

The potential of this discovery has spurred the researchers behind it to establish a company with the aim of developing a new type of immunotherapy for people with various types of cancer.

“In cancer treatment, we need more ways to attack the cancer cells. The complement system is a part of the immune system that is insufficiently activated with current treatment options but has great potential, because it can both respond to the cancer immediately and also create a lasting effect similar to a vaccine. In this study, we found that the complement system can be activated efficiently, and we are now working towards creating a treatment that can be tested in human trials within the next 3 years,” explains a researcher behind the study, Nick Laursen, previously Associate Professor at Aarhus University and now CSO at Commit Biologics, Aarhus. Denmark.

The research has been published in the Journal of Immunology.

The complement system has considerable therapeutic potential

The study focused on activating the part of the immune system called the complement system.

Traditionally, the overall immune system is divided into two parts: the innate and adaptive immune systems.

The innate immune system, which includes the complement system, rapidly responds to microbial threats.

The adaptive immune system is activated by vaccination or infection, learning to recognise a threat and storing knowledge about it so that a microorganism has more difficulty in causing infection again.

The complement system is inherently prepared to respond to threats immediately but also activates the adaptive immune system.

“The complement system bridges the two types of immunity, but even though we have known about this for a long time, it is still not utilised in various types of treatment,” says Nick Laursen.

Binding the immune system to cancer cells

Nick Laursen and colleagues found that the complement system can be activated to attack cancer cells.

The researchers designed a bispecific antibody that can bind to both proteins from the complement system and cancer cells.

The complement system mostly comprises proteins that are part of a large proteolytic cascade with the aim of activating a direct attack against threats and a cellular response.

One of these proteins, C1q, is the first protein in the cascade that ends up creating holes in cells, causing them to burst while activating immune cells that can assist in clearing these cells.

C1q binding to the surface of cells initiates the activation of as many as 30 proteins. Some create the holes in the cells that C1q recognises, and others label the cells. Macrophages and other immune cells recognise these labels and then destroy the pathogenic invaders.

In addition to C1q, the bispecific antibodies the researchers designed also bind to epidermal growth factor receptor, a protein on the surface of cancer cells. The bispecific antibodies thereby pull C1q and the cancer cells together, so that C1q can settle on the surface of the cancer cells and initiate the process that ultimately destroys them.

“The idea is to design a bispecific antibody to recognise something that is only present on the surface of cancer cells, so that the treatment does not target and destroy other cells. Epidermal growth factor receptor is overexpressed on the surface of cancer cells and is necessary for many cancer cells to achieve their extensive growth,” explains Nick Laursen.

Works on cancer cells

The researchers tested the bispecific antibodies on cancer cells and found that they very effectively caused C1q to bind to them, thereby labelling them for immediate destruction.

The bispecific antibodies worked much better than the conventional antibodies some researchers have tried to develop for the same purpose of activating the complement system.

Nick Laursen calls the result a first proof of concept that cancer cells can be attacked by activating the complement system with a bispecific antibody.

The next step is to show that this can work in mice and then among people.

“Many factors influence the response from binding C1q to cancer cells with a bispecific antibody. For example, we must fully control how we optimally recruit C1q and not target other cells. But if and when we achieve our ambitions, we hope to have a treatment that works especially well, because we will activate the entire immune system to combat and eliminate the cancer cells. This means that we both attack the cancer cells immediately by activating the lytic cascade while creating a sustained response that may prevent people from relapsing because their immune system can now identify the cancer cells and know how to attack them,” concludes Nick Laursen.

Commit Biologics has developed a novel platform technology to harness the power of the complement system, a vital part of the innate immune system. Wi...

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