IL-4 AND IL13 SUPERKINES

IL-13 and IL-4 together are critical to the development of Th2 immune responses, which are associated with allergy, asthma, fibrosis and aggressive forms of cancer. In some cancers, a Th2 immune setting actually facilitates cancer growth, as this allows the tumor to co-opt local immune cells into protecting the cancer, rather than fighting it. Both IL-4 and IL-13 participate in the survival and the development of tumor-associated immune cells and an immunosuppressive tumor microenvironment [2]. Thus, altering their ability to drive these responses could be of great benefit to patients suffering from cancer and other Th2 mediated diseases.

These cytokines influence immune cells through a complex arrangement of receptor components[3].

One configuration, known as Type 1 receptor, is specific to IL-4 only, while the other Type 2 receptor configuration can bind either IL-13 or IL-4. A third receptor type will only bind IL-13, but does not activate the immune cell. Instead, it acts as a ‘dummy’ receptor, soaking up IL-13 without incurring any effect on the cell.

This complex interplay between IL-4 and IL-13 can be exploited by Medicenna's Superkine platform to enhance or inhibit the Th2 immune response. IL-4 and IL-13 super-agonists have the ability to reverse Th1 bias typically associated with inflammation and autoimmune diseases such as psoriasis, arthritis, multiple sclerosis including diseases associated with neuro-inflammation such as Alzheimer’s disease.

MDNA132 is a modified IL-13 Superkine that is 16 million times more likely to bind to the ‘dummy’ IL-13 receptor. This particular receptor, known as IL-13Rα2, is not normally expressed on healthy cells, but is highly expressed on some tumors, such as glioblastoma and pancreatic cancer. Due to this wide differential expression pattern, IL-13Rα2, is considered a viable cancer drug target and MDNA132 has been shown to bind this receptor more than 70 times more tightly than drugs such as Zetakine.

MDNA413 is another IL-13 Superkine, but in this case it has an increased affinity for the IL-13Rα1 that forms part of the shared IL-4 and IL-13 Type 2 receptor. This Superkine has a far greater (52-fold) affinity for IL-13Rα1, and a (391-fold) reduced likelihood to bind IL-13Rα2 compared to normal IL-13. The Type 2 receptor is expressed on the immunosuppressive cells of the tumor microenvironment (TME) as well as effector cells associated with Th2 diseases.

This means that it is far more likely to bind the Type 2 receptor than normal IL-13 and is more likely to avoid the dummy receptor. Importantly, MDNA413 then blocks this receptor, preventing it from initiating IL-4 or IL-13 activation within the cell.

Disrupting IL-4 or IL-13 signaling in this way could potentially help treat patients with diseases caused or exacerbated by excessive Th2 responses such as atopic dermatitis, asthma and various forms of fibrosis. Aggressive cancers with a robust TME (“Cold Tumors”) could be transformed to “Hot Tumors” making them susceptible to other cancer immunotherapies such as checkpoint inhibitors and cancer vaccines.

[1] http://www.jimmunol.org/content/192/12/5451.long
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549331/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445396/

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