1-(1-acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia.

1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing blood pressure and improving insulin resistance in pre-diabetic patients. In a mouse model of diet induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hypertension in rats. These effects were dose-dependent and well correlated with inhibition of the sEH activity in whole blood, consistent with a role of sEH in the observed pharmacology in rodents.

In vivo imaging of protease activity by Probody therapeutic activation.

Probody™ therapeutics are recombinant, proteolytically-activated antibody prodrugs, engineered to remain inert until activated locally by tumor-associated proteases. Probody therapeutics exploit the fundamental dysregulation of extracellular protease activity that exists in tumors relative to healthy tissue. Leveraging the ability of a Probody therapeutic to bind its target at the site of disease after proteolytic cleavage, we developed a novel method for profiling protease activity in living animals. Using NIR optical imaging, we demonstrated that a non-labeled anti-EGFR Probody therapeutic can become activated and compete for binding to tumor cells in vivo with a labeled anti-EGFR monoclonal antibody. Furthermore, by inhibiting matriptase activity in vivo with a blocking-matriptase antibody, we show that the ability of the Probody therapeutic to bind EGFR in vivo was dependent on protease activity. These results demonstrate that in vivo imaging of Probody therapeutic activation can be used for screening and characterization of protease activity in living animals, and provide a method that avoids some of the limitations of prior methods. This approach can improve our understanding of the activity of proteases in disease models and help to develop efficient strategies for cancer diagnosis and treatment.

A range of malar and masseteric hypoplasia exists in Treacher Collins syndrome.

BACKGROUND: Treacher Collins syndrome (TCS) is a facial dysostosis, the hallmark being bilateral malar hypoplasia. The purpose of this study is to morphologically classify the TCS malar deformity and to volumetrically characterise both the TCS zygoma and masseter muscle, including for left-right symmetry, compared to controls. We hypothesise that the TCS zygoma will be smaller than controls and zygomatic deficiency will portend masseteric hypoplasia. METHODS: Demographic and computed tomography (CT) data were recorded. The CT scans were converted into three-dimensional facial renderings, and the zygomatic morphology was grossly evaluated. A classification was reported based on malar structure and presence/absence of normal zygomaticomaxillary complex articulations. The zygoma and masseter muscles were then digitally isolated using 3-D planning software (Materialise, Leuven, Belgium). Volumes and sidedness ratios were calculated and compared using two-sided t-tests. RESULTS: 58 sides were identified (24 TCS: 34 controls), mean age of 60.0 months and normally distributed. The phenotypic dysmorphology was graded as mild, moderate or severe (I, II and III, respectively). TCS malar and masseteric volumes were significantly smaller than controls (p < 0.0001 in both cases). The TCS zygomatic side-side symmetry ratio was 0.66 ± 0.28, compared to 0.97 ± 0.02 for controls (p = 0.002). The TCS masseteric side-side ratio was 0.74 ± 0.20, compared to 0.92 ± 0.09 for controls (p = 0.001). CONCLUSIONS: A range of zygomatic hypoplasia exists in TCS (mild-severe). The decrease in malar volume occurs in concert with masseteric hypoplasia, and the left and right sides are not equally affected.

Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index.

Target-mediated toxicity constitutes a major limitation for the development of therapeutic antibodies. To redirect the activity of antibodies recognizing widely distributed targets to the site of disease, we have applied a prodrug strategy to create an epidermal growth factor receptor (EGFR)-directed Probody therapeutic-an antibody that remains masked against antigen binding until activated locally by proteases commonly active in the tumor microenvironment. In vitro, the masked Probody showed diminished antigen binding and cell-based activities, but when activated by appropriate proteases, it regained full activity compared to the parental anti-EGFR antibody cetuximab. In vivo, the Probody was largely inert in the systemic circulation of mice, but was activated within tumor tissue and showed antitumor efficacy that was similar to that of cetuximab. The Probody demonstrated markedly improved safety and increased half-life in nonhuman primates, enabling it to be dosed safely at much higher levels than cetuximab. In addition, we found that both Probody-responsive xenograft tumors and primary tumor samples from patients were capable of activating the Probody ex vivo. Probodies may therefore improve the safety profile of therapeutic antibodies without compromising efficacy of the parental antibody and may enable the wider use of empowered antibody formats such as antibody-drug conjugates and bispecifics.