Th164 - Suppression of Type 2 Inflammatory Responses by Half-life Extended IL-27 in Ovalbumin Induced Delayed Type Hypersensitivity

Thomas Brandt – Immunology Discovery – Janssen Research and Development; Zhao Zhou – Immunology Discovery – Janssen Research and Development; Cailian Li – Immunology Discovery – Janssen Research and Development; Quintus Medley, PhD – Immunology Discovery – Janssen Research and Development; Scott Berger, PhD – Immunology Discovery – Janssen Research and Development; Jennifer Towne, PhD – Immunology Discovery – Janssen Research and Development; Suresh Swaminathan – Translational PK/PD – Janssen Research and Development; Steven Jacobs, PhD – Biophysics – Janssen Research and Development; Lisa Madge, PhD – Immunology Discovery – Janssen Research and Development

Abstract Text: IL-27 (EBI3/p28) is a heterodimeric cytokine with well described regulatory effects on inflammatory T cell responses. These effects include direct suppression of transcriptional regulators such as GATA3 resulting in limited Th2 responses, the induction of coinhibitory receptors and the promotion of Treg specialization and function. To evaluate the regulatory role of IL-27 in vivo, we generated murine half-life extended (HLE)-IL-27. By sub cutaneous (sc) dosing the half-life of the reagent was determined to be approximately 40 hours and resulted in a dose dependent increase in the expression of PDL-1 on CD4 T cells. We evaluated the ability of this reagent to regulate Th2 inflammatory responses in an ovalbumin (OVA)-induced delayed hypersensitivity (DTH) model in BALB/c mice. HLE-IL-27 dosed sc Q2D significantly inhibited OVA induced ear swelling. In serum OVA DTH resulted in increased IL-13 and IgE that was robustly suppressed by HLE-IL-27 while simultaneously increasing IL-10. Profiling of Treg and Teff from draining auricular lymph node demonstrated that HLE-IL-27 increased the ratio of Treg/Teff. Phenotypic modulation of Treg by in the increased expression of PDL-1, CTLA4 and CD39 could also be observed. HLE-IL-27 also decreased the number of GATA3+ CD44+ Teff. Collectively these data demonstrate the multiple suppressive activities resulting from agonism of IL-27R.