The complement system: The driving force behind a new generation of immunotherapies
Immunotherapy is increasingly becoming standard therapy in cancer, with technology, such as checkpoint inhibitors and cell therapy, raising the efficacy bar in many forms of the disease. But the complement system is an oft-overlooked part of the immune system that could be exploited to create new therapies.
It’s more than a decade since the first checkpoint inhibitor hit the market, a revolutionary new therapy approach that works by flipping a biochemical switch, revealing cancer cells to the immune system that had previously been invisible.
This mechanism of action opened up the floodgates, allowing T-cells to do their job and attack tumours. The approach also opened the floodgates for blockbuster-level revenues for drugs such as Merck & Co’s PD-1 inhibitor Keytruda (pembrolizumab).
A few years later, cancer cell therapies hit the market, with CAR-T therapies providing powerful new treatment options for blood cancers. But both approaches have their drawbacks, with checkpoint inhibitors still held back by low response rates, and CAR-Ts limited by issues such as side effects, expense, and their current limitation to blood cancer indications.
Complement and cancer
Scientists are looking for new ways to stimulate the immune system – and the oft-overlooked complement system is becoming of increasing importance.
Complement is a cascade of proteins in the blood that recognises pathogens and marks them for destruction by the rest of the immune system. The system is so named as it is known to “complement” the antibacterial action of antibodies, although it can also be activated in their absence. It’s made up of about 50 proteins that react to “tag” pathogens and induce an inflammatory response that helps to fight infection. The “classical” pathway of the complement system is triggered when C1q binds to antibodies that are already bound to antigens on a cell surface. It only comes into effect when a high number of antibodies are bound to the cell surface, preventing the system from becoming overactive in healthy tissues.
The role of complement in cancer is complex and is dependent on the type of cancer. However, most data indicates that, if the complement system is highly engaged, it has a strong antitumour effect.
If complement is potently activated, it can induce direct killing of the tumour cells by disintegrating the cell membrane. In addition to that, tumour cells will get covered in complement, tagging them for destruction by macrophages and other white blood cells. The complement also sends chemical signals that recruit and activate effector cells that help promote an immune response.
Complement also changes B- and T-cell responses, although tumours may inhibit the system’s influence with complement regulatory proteins (CRPs).
Harnessing the complement system
After realising the potency of the complement system and the link to the adaptive immune system, which can be used to attack tumours, scientists are looking into the potential of stimulating complement to produce an anticancer effect.
It’s the opposite approach to the complement-inhibiting drugs already on the market, such as AstraZeneca/Alexion’s Soliris (eculizumab), which is approved in rare autoimmune diseases where the system has become overactive. For example, Commit Biologics, a biotech based in Aarhus, Denmark, is using an approach with a bispecific “nanobody” – a small antibody derived from those found in camelids that are around a tenth the size of those found in humans and easily converted into bispecific antibodies capable of binding to two different targets.
The thinking is that, by potently activating the complement system, tumour cells will be killed by pores formed in their membrane (also known as complement dependent cytotoxicity, CDC). In addition to this, the cells that are not killed directly by complement will be covered with complement protein fragments that will enable the rest of the immune system to attack the cancer.
Manufacturing should therefore be fairly straightforward
While there are few other competitors stimulating complement to fight cancer, it’s worth noting that existing complement inhibitors have also been proposed in some forms of cancer. One example cited is eculizumab, which inhibits the C5 complement protein and is well known for its use to treat several complement-mediated rare diseases. It’s thought that in some situations complement inhibition will reduce the inflammation that can drive tumour growth.
With immunotherapy response rates still stuck at between 20-30%, there’s a pressing need to find new approaches and possible companion therapies to increase the likelihood of success.
However, Dennis Pederson, Commit’s chief operating officer and co-founder, said: “In cancer, the action of the complement system is context-dependent and low levels of chronic complement activation has in some situations been reported to be pro-tumorigenic, though the data that underpins this concept is not robust and somewhat controversial.”
In the future, there could be applications of complement engagers in both blood cancers and solid tumours, according to Pedersen. He noted that several approved antibodies like ofatumumab and daratumumab have complement activation as a key part of their mechanisms of action.
About the author
Stephen Adams has been an associate director at Optimum Strategic Communications, a specialist life science communications agency, for two years. Prior to that he was a health journalist, spending six years at The Daily Telegraph and then a decade at The Mail on Sunday.
