Cytokines are messenger proteins that transfer signals between cells. They play a crucial role in many processes including haematopoiesis, the formation of the different blood cells, or in the control of an immune response against pathogens or tumours. Some cytokines, like erythropoietin (Epo), are quite successfully used in the clinic, but many others fail because of severe toxicity problems.
AcTakines (Activity-on-Target Cytokines) are detoxified cytokines. In contrast to classical immuno-cytokines, cytokines that are targeted to specific cell types using an antibody against a specific cell surface marker, a mutation that lowers the binding affinity to its cognate receptor complex is added. This way, receptor activation is only observed on the targeted cells, thus dramatically reducing the systemic toxicity of that cytokine. Indeed, a key factor causing generalised toxicities in patients is the ubiquitous expression pattern of receptors, leading to a very complex physiological response when a cytokine is clinically administered.
A prime example is Tumour Necrosis Factor (TNF), a pro-inflammatory cytokine that was originally discovered based on its extraordinary antitumor activity. Its shock-inducing properties, causing hypotension, leukopenia and multiple organ failure, nonetheless prevented its systemic use in cancer treatment. We applied the AcTakine concept on TNF to generate so-called AcTafactors. In this ERC-POC program, we evaluated lead AcTafactors that are being developed in the context of the CYRE ERC Advanced Grant. As expected, we observed a dramatic reduction of toxic side effects, whilst antitumour effects are still maintained.
