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Thomas Waldmann; Immunotherapy targeting IL-2 and IL-15 cytokine receptors. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4768. doi: https://doi.org/.
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Presentation Description :
Disorders of IL-2 and IL-15, cytokine receptors and signaling pathways play a role in the pathogenesis of many autoimmune diseases and lymphoid malignancies. To address these disorders a series of agents have been developed targeting IL-2 and IL-15, cytokine receptors and signaling pathways. In a major collaboration with Dr. Robert Nussenblatt it was shown that daclizumab was of value in treatment of noninfectious intermediate or posterior uveitis. Furthermore, Waldmann and his collaborators demonstrated that daclizumab led to a 78% reduction in gadolinium-enhanced MRI lesions in patients with multiple sclerosis failing interferon beta therapy. These studies were extended by industry and daclizumab (Zinbryta) was approved by the FDA for treatment of patients with multiple sclerosis. In preclinical animal models Dr. Waldmann demonstrated that an abnormality of IL-15/IL-15R plays a role in type 1 diabetes and celiac disease. Waldmann introduced an antibody, Hu Mik-Beta-1 directed to the IL-2/IL-15R beta receptor (CD122) shared by IL-2 and IL-15 that blocks IL-15 action in the treatment of patients with T-LGL leukemia, HTLV-1 associated HAM/TSP and refractory celiac disease. While IL-2 and IL-15 have been shown to be valid therapeutic targets, there are certain failed approaches with a monoclonal antibody identifying a single cytokine receptor. In HTLV-1 associated adult T-cell leukemia the HTLV-1 Tax transactivates both IL-2 and IL-15 and their receptors. Therefore, a strategy in which multiple cytokines are blocked simultaneously is desired. We have evaluated two small molecule agents, BNZ-1 that reacts with γc (CD132) but not IL-2/IL-15R beta (CD122) and H9-RETR that binds tightly to IL-2/IL-15R beta (CD122) but not to γc. These two agents block the access of IL-2 and IL-15 to their receptors and thereby prevent the dimerization of CD122 with γc that is required for signaling. These two agents are being evaluated in preclinical models of T-cell leukemia. Finally, disordered IL-2 and IL-15 actions are being targeted using JAK kinase inhibitors, these include ruxolitinib, a JAK1/2 inhibitor as well as JAK1 and JAK3 specific inhibitors.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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