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Aug 15, 2013
 |  BC Innovations  |  Targets & Mechanisms

IL-17 inhibitors: good news, bad news

New partnerships and release of Phase III data highlight a flurry of activity this summer around the autoimmune target IL-17A. Now, emerging research suggests companies developing inhibitors of IL-17A signaling have both a repurposing opportunity and a new safety concern to navigate.

Findings by the Genentech Inc. unit of Roche suggest IL-17A inhibitors could treat cancers that are resistant to VEGF inhibitors.1 However, an academic team from Sweden and the U.S. reported that blocking IL-17A can destabilize atherosclerotic plaques and thus increase the risk of cardiovascular events.2

IL-17A is a member of the IL-17 family of proinflammatory cytokines, which have roles in allergy and autoimmune diseases. Another member of the family, IL-17F, shares about 50% homology with IL-17A and is involved in airway inflammation in asthma. IL-17A and IL-17F function by binding a heteromeric complex that includes IL-17 receptor (IL17R; IL17RA) and IL-17 receptor C (IL17RC).

Multiple preclinical studies have shown that IL-17 cytokines and Th17 cells-a type of T helper cell that produces the cytokines-in the tumor microenvironment can promote tumor growth or stimulate antitumor immunity, depending on the cancer type and model studied.3 Moreover, the role of IL-17 cytokines in mediating tumor resistance to cancer therapies-such as anti-angiogenics that inhibit signaling between VEGF and VEGF receptor-has been poorly understood.

The Genentech team set out to study the mechanisms by which tumors develop the resistance that blunts the effectiveness of anti-angiogenics. The group started by generating two mouse models-one from a lymphoma cell line that is resistant to VEGF inhibition and the other from a lymphoma cell line that is sensitive to VEGF inhibition.

Levels of Il-17a were higher in the resistant tumors than in the sensitive tumors.

In models with the resistant lymphomas, co-treatment with mouse antibodies against Il-17a and Vegf decreased tumor growth compared with the anti-Vegf antibody...

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