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Cytokine Receptor Signaling Revisited: Implementing novel concepts for cytokine-based therapies

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AcTakines: the next generation of immunotherapy

Immunotherapy is rapidly becoming the fourth pillar in combating cancer, next to surgery, chemo- and radio-therapy. With cytokines failing to show clinical efficacy, European researchers are turning to an innovative approach for addressing cytokine toxicity.

HEALTH

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Cytokines are immune-regulatory proteins governing key physiological processes in the body. Cytokine dysfunction is associated with numerous pathologies including autoimmune disorders and cancer, and cytokines have therefore been exploited for treatment. However, their very spatially restricted activity pattern means that when administered systemically for therapeutic purposes, they cause severe side effects. Cell-specific targeting of cytokines The EU-funded CYRE project proposed to control the spatial distribution of administered cytokines. For this purpose, they developed activity-on-target cytokines (AcTakines), which only unveil their activity on target cells while remaining inactive en route through the body. “Our aim was to support the safe exploitation of the clinical potential of cytokines,″ explains project coordinator Prof. Jan Tavernier. AcTakines consist of a mutant cytokine, with strongly reduced binding affinity for its receptor complex, and a targeting moiety that binds a cell-specific surface marker. This facilitates specific targeting and avoids the systemic toxicity associated with the pleiotropic binding of cytokines. Following proof of principle for structurally diverse cytokines such as type I and II interferons, tumour necrosis factor (TNF) and interleukin-1 (IL-1), CYRE researchers validated the AcTakine effects in vivo in different mouse models for melanoma, lymphoma and breast carcinoma. When targeted to cancer cells or distinct cells of the immune system, efficacy of AcTakines paralleled that of classic cytokines, leading to complete tumour growth arrest but without the undesired side effects. Improved treatment outcome was achieved in combination therapy with doxorubicin or when targeting the tumour vasculature. Apart from minimal toxicity, administration of AcTakines provided anti-tumour immunity. AcTakine merits Looking back in 1980 when as a PhD student he was part of the team that cloned interferon genes, Prof. Tavernier reminisces on the huge expectation the scientific community had for these novel anticancer drugs. Unfortunately, major toxicity issues blunted their full clinical potential. CYRE has demonstrated that the AcTakine concept can in principle be applied to every type of cytokine. By developing AcTakines for structurally different types of cytokines, scientists have demonstrated that the intrinsic toxicity of cytokines can now be controlled. The single cell-type targeting precision of AcTakines renders them safe for systemic administration while preserving their therapeutic potential. AcTakines can be used to treat a very broad range of cancers, reducing the overall clinical development costs. Importantly, since they do not necessarily target the tumour cells themselves, resistance to therapy will be significantly lower compared to traditional anti-cancer drugs. To take AcTakines from bench to bedside, Prof. Tavernier co-founded with Nikolai Kley a spin-off company called Orionis Biosciences. The company that now also operates across the Atlantic has built a very extensive IP portfolio covering many aspects of the AcTakine platform. Selected AcTakines with optimised pharmaceutical properties for human use are already in the production phase. According to Tavernier, further clinical development in collaboration with key pharma companies in the immunotherapy field will facilitate the phase I clinical trials, which are expected to commence by the end of 2020. In view of the future, Prof. Tavernier is confident, that “AcTakines will make their way to the clinic for a broad range of diseases beyond cancer, including many autoimmune disorders.″ With immunotherapy currently focusing on targeted antibodies, immune checkpoint inhibitors, and cell-based therapies, AcTakines will help revive the therapeutic potential of cytokines.

Keywords

CYRE, AcTakines, cytokines, cancer, toxicity, immunotherapy, autoimmune

Project information

Grant agreement ID: 340941

Status

Closed project

  • Start date

    1 February 2014

  • End date

    31 January 2019

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 2 487 728,40

  • EU contribution

    € 2 487 728,40

Hosted by:

VIB