Cytokine fusion proteins

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Next-generation antibody therapeutics promising to revolutionise cancer treatment

Over the past three decades, a group of medicines known as therapeutic antibodies has improved the treatment of difficult-to-treat diseases such as cancer, viral infections and inflammatory diseases, due to their unique ability to “home in” on specific proteins found on the surface of cells.

Now, a new era of next-generation engineered therapeutic antibodies e.g. complex targeted or bispecific antibodies is emerging, that hopefully improve on the standard monoclonal antibody format that has been used to date.

One of these new engineered formats is the cytokine fusion protein, or Immunocytokine. For decades, attempts to tap into the powerful immune-stimulating properties of cytokines in the fight against cancer have been derailed by lack of targeting to the tumour and toxicities in the body due to uncontrolled immune reactions.

“At Roche, we have believed for a long time that cancer immunotherapies could be a powerful, transformative approach to controlling tumours. Cytokines such as interleukins or interferons are proteins naturally made by the body to activate and regulate the immune system to fight infections or tumour formation. We addressed the question how we could engineer cytokines to better use their powerful immune-stimulating properties while minimising their known side effects. This led us to look into the field of specifically delivering cytokines into the tumour to stimulate the immune system locally to attack cancer cells,” says Pablo Umaña, Head of Cancer Immunotherapy Discovery at the Roche Innovation Centre in Zurich.

“Cytokine fusion proteins combine an engineered cytokine with an antibody against a defined surface target on cancer cells. The engineered cytokine is intended to reduce the activation of undesired immunosuppressive T cells (so-called Tregs) and to reduce the toxicities that have been seen in the past. Furthermore attaching a single engineered cytokine to an antibody may allow better tumour targeting due to higher affinity for the tumour cell rather than the immune cell, and thus a hopefully more controlled immune reaction directly in the tumour but not in non-tumorous tissues in the body. Once the antibody has delivered the cytokine into the tumour, immune cells such as natural or T killer cells that can recognise and kill the cancer cell would be activated and then proliferate,” explains Christian Klein, Preclinical Project Leader for the cytokine fusion protein development programme.

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What sounds like an easy process is in reality technically very complex. As Markus Neubauer from the Large Molecule Research team at the Roche Innovation Centre in Penzberg explains: “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.”

In order to produce such a cytokine fusion protein at a large scale and in high quality, an innovative development strategy that included state-of-the-art high-throughput cell line screening and analytical methods was required. With this approach, Roche scientists were able to achieve a favourable product pattern using a cell line as applied for conventional antibodies. It took intensive work from a lot of creative, talented and very resilient people at the Roche Innovation Centres in Zurich, Penzberg and Shanghai to discover and develop these novel cytokine fusion proteins from the initial concept to clinical trials.

If proven successful, such molecules could be the basis for novel combination immunotherapies and trigger the development of a novel class of cytokine fusion proteins.

Tags: Biotechnology