Collectively, our studies indicate that a 5 day model of IL-23 psoriasiform dermatitis can be used to assess the pharmacology of novel small molecules/biologics in the treatment of PsO.

Background: Obese ZSF-1 rats display many features of human type II diabetes including nephropathy (DN). The study aimed to further understand the relevance of this model to DN, for which glomerular filtration rate (GFR), renal fibrosis and several urinary/tissue biomarkers was followed over 24 weeks in ZSF-1 rats. Methods: Intact/sham or uninephrectomized male and female ZSF-1 rats were studied. GFR was measured by transdermal clearance of fluorescein isothiocyanate-sinistrin. Urine was collected every 2-4 weeks for biomarker analysis. Renal tissue was examined histologically for fibrosis and for levels of inflammatory and fibrotic genes. Results: Male obese ZSF-1 rats demonstrated metabolic syndrome and proteinuria. Female counterparts were hyperlipidemic with delayed proteinuria, but were not hyperglycemic. Kidney hyperfiltration was observed in male obese rats in weeks 2-4 after surgery, and subsequently declined to levels significantly lower than controls. Tubulointerstitial/glomerular fibrosis in male obese rats was significantly elevated by week 12 post surgery and continued to expand in the ensuing weeks, particularly in uninephrectomized rats. Female rats had less severe fibrosis. Except for epidermal growth factor which decreased, the levels of several key inflammatory, injury and fibrotic factors were elevated in both tissue (mRNA) and urine (protein) of male obese rats. Conclusion: Male obese ZSF-1 rats represent an important DN model, manifesting key pathophysiological features including metabolic syndrome, proteinuria, progressive tubular and glomerular fibrosis, and transient hyperfiltration followed by progressive decline in renal function. Uninephrectomy significantly accelerated disease progression. Females were less severe in disease manifestation. Several urinary and tissue biomarkers were identified in the male obese rats that tracked with disease progression.

Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of renal fibrosis, injury induced significant upregulation of FnEDA in the obstructed kidney. Using dual variable domain Ig (DVD-Ig) technology, we constructed a molecule with a moiety to target FnEDA and a second moiety to neutralize TGF- After systemic injection of the bispecific TGF- + FnEDA DVD-Ig or an FnEDA mAb, chemiluminescent detection and imaging with whole-body single-photon emission computed tomography (SPECT) revealed significantly higher levels of each molecule in the obstructed kidney than in the nonobstructed kidney, the ipsilateral kidney of sham animals, and other tissues. In comparison, a systemically administered TGF- mAb accumulated at lower concentrations in the obstructed kidney and exhibited a more diffuse whole-body distribution. Systemic administration of the bispecific DVD-Ig or the TGF- mAb (1-10 mg/kg) but not the FnEDA mAb attenuated the injury-induced collagen deposition detected by immunohistochemistry and elevation in Col1a1, FnEDA, and TIMP1 mRNA expression in the obstructed kidney. Overall, systemic delivery of a bispecific molecule targeting an extracellular matrix protein and delivering a TGF- mAb resulted in a relatively focal uptake in the fibrotic kidney and reduced renal fibrosis.

Background Anti-cytokine therapies have become the mainstay of treatment for rheumatoid arthritis (RA) disease symptoms and can arrest disease progression. Despite numerous treatment options there are still many RA patients who fail to experience substantial decreases in disease activity. Recently, Jak kinase blockade was shown clinically to be effective in managing disease and in some cases achieving remission. However, these first generation Jak inhibitors have failed to meet expectations due to dose-limiting tolerability and safety issues. ABT-494 is a second generation Jak kinase inhibitor with high selectivity for Jak1 thereby minimizing the potential for side effects related to Jak2 and Jak3 inhibition. Here we describe preclinical and early clinical data that suggest ABT-494 has potential to address some of the current unmet medical needs of RA patients. Methods ABT-494 was engineered for increased selectivity for Jak1 using structural predictions that indicated the potential for differential binding interactions outside the ATP-binding active site of Jak1 but not Jak2. The efficacy and selectivity of ABT-494 were tested in a battery of relevant cellular and in vivo pharmacology assays including bone marrow colony formation, adjuvant induced arthritis (AIA), erythropoietin induced reticulocyte deployment and NK/NKT cell suppression. The potency of ABT-494 in a variety of complementary pharmacodynamic assays was also assessed at multiple dosages in healthy human subjects administered orally for 14 days. Results ABT-494 demonstrates approximately 74 fold selectivity for Jak1 over Jak2 in cellular assays dependent on specific, relevant cytokines. ABT-494 is a potent inhibitor of inflammation and bone loss in rat AIA and, compared to Tofacitinib, spares relevant essential physiological processes such as erythropoietin signaling and peripheral NK cell counts at similarly efficacious doses in rats. When dosed orally for 14 days in healthy human subjects ABT-494 did not decrease reticulocyte or NK cell counts at predicted efficacious doses consistent with its pharmacodynamic properties in rats. Conclusions ABT-494 is a Jak1-selective inhibitor that demonstrates efficacy in rat arthritis models. Preliminary evidence suggests that pharmacodynamic properties of ABT-494 are consistent between those observed in rodent models and in healthy human subjects. Taken together, these encouraging observations support further testing of ABT-494 in RA patients in Phase II randomized placebo controlled trials and indicate it may have increased potential to address patient needs over existing agents. Disclosure of Interest : J. Voss Employee of: AbbVie, C. Graff Employee of: AbbVie, A. Schwartz Employee of: AbbVie, D. Hyland Employee of: AbbVie, M. Argiriadi Employee of: AbbVie, H. Camp Employee of: AbbVie, L. Dowding Employee of: AbbVie, M. Friedman Employee of: AbbVie, K. Frank Employee of: AbbVie, J. George Employee of: AbbVie, E. Goedken Employee of: AbbVie, G. Lo Schiavo: None declared, M. Morytko Employee of: AbbVi...