Over 30 years ago, scientists developed a group of medicines known as therapeutic antibodies. These molecules have a unique ability to “home in” on and bind to single targets on diseased cells like cancer tumours. The engineering of therapeutic antibodies was a step forward in the evolution of personalised healthcare and accelerated innovation in cancer treatment.

Now, scientists are working on engineering the next generation of therapeutic antibodies including ‘bispecific’ antibodies. These antibodies can bind to two targets at once and the hope is that this dual binding ability will harness the immune system in a much more targeted way and lead to better treatment outcomes for patients. One of these novel engineered molecules is the cytokine fusion protein, or Immunocytokine.

Cytokines are cell-signalling proteins that are naturally made by the body to activate and regulate the immune system. “At Roche, we have believed for a long time that cancer immunotherapies could be a powerful, transformative approach to controlling tumours,” says Pablo Umaña, Head of Cancer Immunotherapy Discovery at the Roche Innovation Centre in Zurich.

The team first had to overcome the cytokines’ inability to specifically target the cancer cells, which can lead to broad immune reactions and toxicities in the body. “We set out to answer how we could engineer cytokines to better use their powerful immune-stimulating properties while minimising their known side effects,” says Pablo Umaña. This led them to look into the possibility of specifically delivering cytokines into the tumour, which would activate the immune system locally to attack the cancer cells.

The benefits of fusing a cytokine with an antibody

The team found that attaching a single engineered cytokine to an antibody may allow better tumour targeting due to higher affinity towards the cancer cell rather than the immune cell. According to Christian Klein, Preclinical Project Leader for the cytokine fusion protein development programme, “The engineered cytokine is intended to reduce the activation of undesired immunosuppressive T cells (so-called Tregs) and to reduce the toxicities seen in the past. We believe this will hopefully result in a more controlled immune reaction directly at the tumour.”

Once the antibody has delivered the cytokine into the tumour, immune cells that can recognise and kill the cancer cell like T cells or natural killer cells would be activated.

A deceptively simple concept requiring global teamwork

What sounds like an easy process is in reality technically very complex.

“The antibody is engineered asymmetrically in order to attach only one single engineered cytokine to the antibody to increase the drug’s targeting to the tumour,” says Markus Neubauer from the Large Molecule Research team at the Roche Innovation Centre in Penzberg.

Producing such a cytokine fusion protein on a large scale and to a high enough quality required an innovative development strategy that included state-of-the-art high-throughput cell line screening and analytical methods. It took intensive and collaborative work from many creative, talented and resilient people at the Roche Innovation Centers in Zurich, Munich and Basel to discover and develop these novel molecules from the initial concept to clinical trials.

If proven successful, cytokine fusion proteins could be the basis for new combination treatments, hopefully offering patients additional treatment options whilst encouraging further scientific discovery.

Tags: Science, Biotechnology