Detector size selection for long-range targeting performance in the extended shortwave infrared band.

Interest in the eSWIR band is growing due to focal plane array technology advancements with mercury cadmium telluride and type-II superlattice materials. As design and fabrication processes improve, eSWIR detector size, weight, and power can now be optimized. For some applications, it is desirable to have a smaller detector size. Reduced solar illumination in the 2 to 2.5 µm spectral range creates a fundamental limit to passive imaging performance in the eSWIR band where the resolution benefit of small detectors cannot out-compete the reduced SNR in photon-starved environments. This research explores the underlying theory using signal-to-noise ratio radiometry and modeled target discrimination performance to assess the optimal detector size for eSWIR dependent upon illumination conditions. Finally, we model continuous-wave laser illumination in the eSWIR band to compare the effect of detector size on active and passive imaging for long-range object discrimination.

Comparison of reflective band (Vis, NIR, SWIR, eSWIR) performance in daytime reduced illumination conditions.

Daytime low-light conditions such as overcast, dawn, and dusk pose a challenge for object discrimination in the reflective bands, where the majority of illumination comes from reflected solar light. In reduced-illumination conditions, the sensor signal-to-noise ratio can suffer, inhibiting range performance for detecting, recognizing, and identifying objects of interest. This performance reduction is more apparent in the longer wavelengths where there is less solar light. Range performance models show a strong dependence on cloud type and thickness, as well as time of day across the reflective wavebands. Through an experimental and theoretical analysis of a passive sensitivity- and resolution-matched testbed, we compare Vis (0.4-0.7 µm), NIR (0.7-1 µm), SWIR (1-1.7 µm), and eSWIR (2-2.5 µm) to assess the limiting cases in which reduced illumination inhibits range performance. The time during dawn and dusk is brief yet does show significant range performance reduction for SWIR and eSWIR. Under heavy cloud cover, eSWIR suffers the most at range due to a low signal-to-noise ratio. In cases of severe reduction in illumination, we propose utilizing active illumination or the emissive component of eSWIR to improve the signal-to-noise ratio for various discrimination tasks.

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494).

BACKGROUND: Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. METHODS: Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. RESULTS: Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. CONCLUSIONS: The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile.

RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study.

INTRODUCTION: A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study. METHODS: Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma. RESULTS: In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo. CONCLUSION: RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis). FUNDING: AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript.