Safety, tolerability, pharmacokinetics and efficacy of HB0017, a humanized monoclonal antibody that targets interleukin-17A, in healthy participants and patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Several interleukin (IL)-17 inhibitors have been approved for the treatment of moderate-to-severe plaque psoriasis (PsO). There is still scope for the development of affordable treatments for PsO. OBJECTIVES: To assess, in a phase Ia study, the safety, tolerability and pharmacokinetics (PK) of HB0017, a humanized monoclonal antibody that targets IL-17A, in healthy participants and patients with moderate-to-severe plaque PsO; and, in a phase Ib study, to assess the efficacy of HB0017 in patients with moderate-to-severe plaque PsO. METHODS: The phase Ia study (NCT04505033) was a randomized double-blind placebo-controlled dose-escalation study in healthy participants. Each cohort of 10 volunteers was randomly assigned to receive either a single dose of HB0017 (50 mg, 150 mg, 300 mg or 450 mg) or the matching placebo at a ratio of 4 : 1. The phase Ib study (NCT05442788) was a randomized double-blind placebo-controlled dose-escalation study in enrolled patients with moderate-to-severe plaque PsO. Each cohort of 10 patients was randomly assigned to receive either multiple doses of HB0017 (150 mg, 300 mg or 450 mg) or the matching placebo at a ratio of 4 : 1. RESULTS: HB0017 demonstrated dose-proportional linear PK and was tolerated across the dose range assessed. In the phase Ia and Ib studies, participants in both the HB0017 and placebo groups experienced treatment-emergent adverse events (69% vs. 87%, 96% vs. 100%, respectively). HB0017 demonstrated clinically meaningful effects in patients with moderate-to-severe plaque PsO. PASI 75 [≥ 75% improvement in Psoriasis Area and Severity Index (PASI)], PASI 90 (≥ 90% improvement in PASI) and static Physician Global Assessment (sPGA) 0/1 (i.e. 'clear' or 'almost clear') responses were 100% for the HB0017 300-mg group, with maximal improvements (100% or near 100% reductions from baseline) in PASI score observed at week 12, while the duration of effect was evident up to week 20. There was no clinical response in any participant in the placebo group in the phase Ib study. CONCLUSIONS: Overall, HB0017 showed acceptable safety and tolerability in both healthy participants and patients with moderate-to-severe plaque PsO. An encouraging signal of efficacy with a longer half-life provides HB0017 with the potential to be added to the currently available range of biologics targeting IL-17A.

Sparse Representation Based Frequency Detection and Uncertainty Reduction in Blade Tip Timing Measurement for Multi-Mode Blade Vibration Monitoring.

The accurate monitoring of blade vibration under operating conditions is essential in turbo-machinery testing. Blade tip timing (BTT) is a promising non-contact technique for the measurement of blade vibrations. However, the BTT sampling data are inherently under-sampled and contaminated with several measurement uncertainties. How to recover frequency spectra of blade vibrations though processing these under-sampled biased signals is a bottleneck problem. A novel method of BTT signal processing for alleviating measurement uncertainties in recovery of multi-mode blade vibration frequency spectrum is proposed in this paper. The method can be divided into four phases. First, a single measurement vector model is built by exploiting that the blade vibration signals are sparse in frequency spectra. Secondly, the uniqueness of the nonnegative sparse solution is studied to achieve the vibration frequency spectrum. Thirdly, typical sources of BTT measurement uncertainties are quantitatively analyzed. Finally, an improved vibration frequency spectra recovery method is proposed to get a guaranteed level of sparse solution when measurement results are biased. Simulations and experiments are performed to prove the feasibility of the proposed method. The most outstanding advantage is that this method can prevent the recovered multi-mode vibration spectra from being affected by BTT measurement uncertainties without increasing the probe number.

Analysis of the Dynamic Sensitivity of Hemisphere-Shaped Electrostatic Sensors' Circular Array for Charged Particle Monitoring.

Electrostatic sensor arrays (ESAs) are promising in industrial applications related to charged particle monitoring. Sensitivity is a fundamental and commonly-used sensing characteristic of an ESA. However, the usually used spatial sensitivity, which is called static sensitivity here, is not proper for moving particles or capable of reflecting array signal processing algorithms integrated in an ESA. Besides, reports on ESAs for intermittent particles are scarce yet, especially lacking suitable array signal processing algorithms. To solve the problems, the dynamic sensitivity of ESA is proposed, and a hemisphere-shaped electrostatic sensors' circular array (HSESCA) along with its application in intermittent particle monitoring are taken as an example. In detail, a sensing model of the HSESCA is built. On this basis, its array signals are analyzed; the dynamic sensitivity is thereupon defined by analyzing the processing of the array signals. Besides, a component extraction-based array signal processing algorithm for intermittent particles is proposed, and the corresponding dynamic sensitivity is analyzed quantitatively. Moreover, simulated and experimental results are discussed, which validate the accuracy of the models and the effectiveness of the relevant approaches. The proposed dynamic sensitivity of ESA, as well as the array signal processing algorithm are expected to provide references in modeling, designing and using ESAs.

Optimal Sequential Diagnostic Strategy Generation Considering Test Placement Cost for Multimode Systems.

Sequential fault diagnosis is an approach that realizes fault isolation by executing the optimal test step by step. The strategy used, i.e., the sequential diagnostic strategy, has great influence on diagnostic accuracy and cost. Optimal sequential diagnostic strategy generation is an important step in the process of diagnosis system construction, which has been studied extensively in the literature. However, previous algorithms either are designed for single mode systems or do not consider test placement cost. They are not suitable to solve the sequential diagnostic strategy generation problem considering test placement cost for multimode systems. Therefore, this problem is studied in this paper. A formulation is presented. Two algorithms are proposed, one of which is realized by system transformation and the other is newly designed. Extensive simulations are carried out to test the effectiveness of the algorithms. A real-world system is also presented. All the results show that both of them have the ability to solve the diagnostic strategy generation problem, and they have different characteristics.

A non-uniformly under-sampled blade tip-timing signal reconstruction method for blade vibration monitoring.

High-speed blades are often prone to fatigue due to severe blade vibrations. In particular, synchronous vibrations can cause irreversible damages to the blade. Blade tip-timing methods (BTT) have become a promising way to monitor blade vibrations. However, synchronous vibrations are unsuitably monitored by uniform BTT sampling. Therefore, non-equally mounted probes have been used, which will result in the non-uniformity of the sampling signal. Since under-sampling is an intrinsic drawback of BTT methods, how to analyze non-uniformly under-sampled BTT signals is a big challenge. In this paper, a novel reconstruction method for non-uniformly under-sampled BTT data is presented. The method is based on the periodically non-uniform sampling theorem. Firstly, a mathematical model of a non-uniform BTT sampling process is built. It can be treated as the sum of certain uniform sample streams. For each stream, an interpolating function is required to prevent aliasing in the reconstructed signal. Secondly, simultaneous equations of all interpolating functions in each sub-band are built and corresponding solutions are ultimately derived to remove unwanted replicas of the original signal caused by the sampling, which may overlay the original signal. In the end, numerical simulations and experiments are carried out to validate the feasibility of the proposed method. The results demonstrate the accuracy of the reconstructed signal depends on the sampling frequency, the blade vibration frequency, the blade vibration bandwidth, the probe static offset and the number of samples. In practice, both types of blade vibration signals can be particularly reconstructed by non-uniform BTT data acquired from only two probes.

Analytical and numerical investigations into hemisphere-shaped electrostatic sensors.

Electrostatic sensors have been widely used in many applications due to their advantages of low cost and robustness. Their spatial sensitivity and time-frequency characteristics are two important performance parameters. In this paper, an analytical model of the induced charge on a novel hemisphere-shaped electrostatic sensor was presented to investigate its accurate sensing characteristics. Firstly a Poisson model was built for electric fields produced by charged particles. Then the spatial sensitivity and time-frequency response functions were directly derived by the Green function. Finally, numerical calculations were done to validate the theoretical results. The results demonstrate that the hemisphere-shaped sensors have highly 3D-symmetrical spatial sensitivity expressed in terms of elementary function, and the spatial sensitivity is higher and less homogeneous near the hemispherical surface and vice versa. Additionally, the whole monitoring system, consisting of an electrostatic probe and a signal conditioner circuit, acts as a band-pass filter. The time-frequency characteristics depend strongly on the spatial position and velocity of the charged particle, the radius of the probe as well as the equivalent resistance and capacitance of the circuit.

Single-sensor rotating blade monitoring method under non-stationary conditions based on velocity and displacement.

A novel single-sensor method for monitoring rotating blade vibration is proposed and utilized to identify vibration parameters under the non-stationary condition. By analyzing the pulse-signal waveform, the blade tip displacement and vibration velocity are extracted. Then, the motion equation under the non-stationary condition is further developed to provide a theoretical basis. Finally, the optimization technology is applied to extract vibration parameters. Compared with multiple-sensor methods, the proposed method has lower installation difficulty, less equipment cost, fewer sensors, and no strict sensor layout requirement. Numerical simulations and experiments are conducted to validate the effectiveness and robustness of the proposed method. The relative error in the natural frequency does not exceed 0.1 %. Additionally, errors in other parameters are less than 8 % in the experiment.

MicroRNA-based therapy for glioblastoma: Opportunities and challenges.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor and is characterized by high mortality and morbidity rates and unpredictable clinical behavior. The disappointing prognosis for patients with GBM even after surgery and postoperative radiation and chemotherapy has fueled the search for specific targets to provide new insights into the development of modern therapies. MicroRNAs (miRNAs/miRs) act as oncomirs and tumor suppressors to posttranscriptionally regulate the expression of various genes and silence many target genes involved in cell proliferation, the cell cycle, apoptosis, invasion, stem cell behavior, angiogenesis, the microenvironment and chemo- and radiotherapy resistance, which makes them attractive candidates as prognostic biomarkers and therapeutic targets or agents to advance GBM therapeutics. However, one of the major challenges of successful miRNA-based therapy is the need for an effective and safe system to deliver therapeutic compounds to specific tumor cells or tissues in vivo, particularly systems that can cross the blood-brain barrier (BBB). This challenge has shifted gradually as progress has been achieved in identifying novel tumor-related miRNAs and their targets, as well as the development of nanoparticles (NPs) as new carriers to deliver therapeutic compounds. Here, we provide an up-to-date summary (in recent 5 years) of the current knowledge of GBM-related oncomirs, tumor suppressors and microenvironmental miRNAs, with a focus on their potential applications as prognostic biomarkers and therapeutic targets, as well as recent advances in the development of carriers for nontoxic miRNA-based therapy delivery systems and how they can be adapted for therapy.

A Randomized, Double-Blind, Single-Dose Study Comparing the Biosimilarity of HOT-1010 With Bevacizumab (Avastin®) in Chinese Healthy Male Subjects.

Objective: This study was conducted to compare the pharmacokinetics, safety and immunogenicity of HOT-1010 with bevacizumab (Avastin®) in Chinese healthy male subjects. Methods: A single-center, randomized, double-blind, single-dose, parallel trial was performed in 84 Chinese healthy male subjects who randomly (1:1) received a single intravenous infusion of 1 mg/kg HOT-1010 or Avastin® for 90 min and followed up for 85 days. Serum concentrations of bevacizumab were analyzed by enzyme-linked immunosorbent assay. Primary pharmacokinetic parameters, Cmax, AUC0-t and AUC0-∞, were calculated and evaluated the bioequivalence between HOT-1010 and Avastin®, the safety and immunogenicity of investigational drugs were also assessed. Results: A total of 82 subjects completed the study. The 90% Confidence Intervals for geometric mean ratios of Cmax, AUC0-t and AUC0-∞ were 91.81-103.64%, 85.19-95.39% and 85.04-95.36%, which were all within the bioequivalence margin. Treatment-emergent adverse events were reported in 27 (65.9%) subjects in HOT-1010 group and 23 (56.1%) subjects in Avastin® group. Most TEAEs were mild or moderate. No TEAEs, Serious Adverse Events or deaths leading to discontinuation was reported. Subjects were all tested negative for Anti-drug Antibody. Conclusion: HOT-1010 exhibited the similar pharmacokinetics, safety and immunogenicity profiles of bevacizumab (Avastin®) in Chinese healthy male subjects. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html, CTR20181610.

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of HOT-3010 to Adalimumab Among Healthy Chinese Male Subjects.

Objective: This study explored the bioequivalence of a proposed biosimilar HOT-3010 vs. its reference product (adalimumab) among healthy Chinese male subjects. The study also investigated the tolerance, immunogenicity, and pharmacokinetics (PK). Methods: A randomized, double-blind, two-arm, parallel study was performed to examine the bioequivalence of HOT-3010 (40 mg) with that of adalimumab (Humira®, AbbVie) as a reference drug. The study subjects were followed up for 71 days. Results: PK properties exhibited by HOT-3010 (N = 66) and adalimumab (N = 68) groups were similar. The 90% confidence intervals of the ratios for C max, AUC0-t , and AUC0∞ were observed to be in the range 80-125% on comparing the two groups. For anti-drug antibodies (ADA), the number of subjects found to be positive in the HOT-3010 group and adalimumab group were 29 (43.94%) and 32 (47.06%), whereas 27 (40.91%) and 27 (39.71%) subjects were found to be positive for NAb, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were recorded in 32 subjects each in both the groups, respectively. Conclusion: The PK characteristics and immunogenicity exhibited by HOT-3010 were similar to that of the reference product, adalimumab. The safety profiles were similar in both the treatment groups with mild-moderate adverse effects.

Erratum: Li, Z.; Zhang, W.; Wang, R.; Chen, F.; Jia, X.; Cong, P. Effects of Reactive MgO on the Reaction Process of Geopolymer. Materials 2019, 12, 526.

Author Contributions: Conceptualization, Z [...].

Selection of IgE-binding aptameric green fluorescent protein (Ap-GFP) by the ribosome display (RD) platform.

GFP-Ckappa fusion protein was previously shown selectable on ribosome display platform with solid phase antibodies against GFP determinant [Y.-M. Yang, T.J. Barankiewicz, M. He, M. Taussig, S.-S. Chen, Selection of antigenic markers on a GFP-Ckappa fusion scaffold with high sensitivity by eukaryotic ribosome display, Biochem. Biophys. Res. Commun. 359 (2007) 251-257]. Herein, we show that members of aptameric peptide library constructed within the site 6 and site 8/9 loops of GFP of the ribosome display construct are selectable upon binding to the solid phase IgE antigen. An input of 1.0 microg of the dual site aptameric GFP library exhibiting a diversity of 7.5x10(11) was transcribed, translated and incubated with solid phase IgE. RT-PCR products were amplified from mRNA of the aptamer-ribosome-mRNA (ARM) complex captured on the solid phase IgE. Clones of aptameric GFP were prepared from RT-PCR product of ARM complex following repetitive selection. Recombinant aptameric GFP proteins from the selected clones bind IgE coated on the 96-well plate, and the binding was abrogated by incubation with soluble human IgE but not human IgG. Selected aptameric GFP proteins also exhibit binding to three different sources of human IgE (IgE PS, BED, and JW8) but not irrelevant proteins. These observations indicate that appropriately selected aptameric GFP on a solid phase ligand by ribosome display may serve as an affinity reagent for blocking reactivity of a biological ligand.

Protection of IgE-mediated allergic sensitization by active immunization with IgE loops constrained in GFP protein scaffold.

Green fluorescent protein (GFP) exhibits a rigid central beta-barrel, formed by eleven beta-strands with floppy loops spanning between the stands. Herein, we evaluate whether the rigid beta-barrel may serve as a scaffold that can constrain the loops of a foreign protein, and thus its antigenicity. The spanning loops, site 6 of GFP, were engineered with RE cloning sites for inserting oligonucleotides corresponding to FcepsilonRI-binding sequence of human IgE. In a high-throughput format, shortened oligonucleotides encoding eight amino acid residues of the receptor-binding regions were inserted into site 6 of GFP by PCR, followed by enabling sequences for in vitro transcription and translation at the 5' end. Antigenized C2-3 linker (C2-3L) was shown by immuno-blots with polyclonal anti-IgE under native gel electrophoresis and transfer. Recombinant antigenized GFP was expressed and purified to homogeneity by metal affinity column, followed by Sephacryl S-200 high resolution gel filtration. Hyperimmune sera from mice immunized with C2-3L antigenized GFP contain anti-IgE reactive with JW8 murine/human chimeric IgE. Further, elevated serum anti-C2-3L and affinity pure antibodies effectively inhibits binding of JW8 IgE to recombinant FcepsilonRIalpha, and desensitizes JW8 to rat RBL-2H3 transfected with human FcepsilonRIalpha. This observation raised the possibility that active IgE vaccine may be employed in raising active protective anti-IgE in allergic patients as an alternative to passive immunization with MAb-E25 anti-IgE. Taken together, GFP appears suitable protein scaffold for spanning/constraining the C2-3L of human IgE as active vaccine; and this technique may be generally employed for eliciting antibodies to specific B-cell epitopes of other proteins.

IgE peptide-specific CTL inhibit IgE production: a transient IgE suppression model in wild-type and HLA-A2.1 transgenic mice.

Effect of IgE peptide-specific CTL on IgE antibody production was studied in mouse models. CTL elicited in B6.A2Kb tg mice against a human IgE peptide nonamer, pWV, lysed human IgE-secreting U266 myeloma cells and inhibit IgE production by these cells. U266 transfected with mouse A2Kb transgene (U266-A2Kb) were optimally lysed by these CTL, because the alpha3 domain of A2Kb interacts well with the CD8 co-receptors. The CTL generated were more effective in inhibiting IgE production by U266-A2Kb cells than lysing these cells. IgE production by and progression of U266 myeloma were suppressed in B6.A2Kb tg mice rendered tolerant to these cells and vaccinated with pWV along with CpG. We also studied the CTL response elicited in wild-type mice by a mouse nonameric IgE peptide, PI-1, along with CpG. This treatment caused a transient suppression of the IgE response in mice previously sensitized to an antigen. In mice treated with this regimen repeatedly, the IgE response was fully recovered 20 days after each treatment. Notably, while IgE peptide/CpG-treated mice remained unresponsive to antigen challenge in vivo, antigen-specific IgE production can be elicited by antigen in cultured splenocytes from these mice. Moreover, IgE peptide/CpG also inhibited an on-going IgE response, including IgE production by bone marrow cells. Taken together, these observations indicate that a CTL-based IgE peptide vaccine targeting IgE-secreting B/plasma cells may be safely employed as a therapeutic approach for suppressing IgE production.

C-Jun NH(2)-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma.

PURPOSE: C-Jun NH(2)-terminal kinase (JNK) has been implicated in numerous functions including stress responses, apoptosis,and transformation. The role in transformation is based largely on studies of isolated cell types with little indication of whether JNK plays a general role in a specific human tumor type or whether this occurs in vivo. EXPERIMENTAL DESIGN: We examined 9 human prostate carcinoma cell lines in vitro and a representative line in vivo. RESULTS: For all of the cell lines proliferation is highly correlated with serum-supported JNK activity (r(Pearson) = 0.91; P = 0.004), whereas no relationship was observed for 10 human breast cancer cell lines (r(Pearson) = -0.32). Treatment with characterized antisense oligonucleotides complementary to sequences common to either the JNK1 or JNK2 family of isoforms showed that, whereas antisense JNK1 inhibited growth by a maximum of 57%, antisense JNK2 inhibited proliferation up to 80%. Sense and scrambled control oligonucleotides had little effect (average 3.7 +/- 1.5%). Moreover, systemic treatment of mice bearing established xenografts of PC3 prostate carcinoma cells with antisense JNK1 and JNK2 led to inhibition tumor growth by 57% (P < 0.002) and 80% (P < 0.001), respectively. The difference is significant (P < 0.012). Combined antisense treatment led to a significant increase in frequency of tumor regression (P = 0.022). CONCLUSION: These results indicate that JNK is required for growth of prostate carcinoma cells in vitro and in vivo, and additionally indicate that JNK2 plays a dominant role. The JNK pathway is a novel target in the treatment of prostate carcinoma.

Self-tuning wireless power transmission scheme based on on-line scattering parameters measurement and two-side power matching.

Sub-resonances often happen in wireless power transmission (WPT) systems using coupled magnetic resonances (CMR) due to environmental changes, coil movements or component degradations, which is a serious challenge for high efficiency power transmission. Thus self-tuning is very significant to keep WPT systems following strongly magnetic resonant conditions in practice. Traditional coupled-mode ways is difficult to solve this problem. In this paper a two-port power wave model is presented, where power matching and the overall systemic power transmission efficiency are firstly defined by scattering (S) parameters. Then we propose a novel self-tuning scheme based on on-line S parameters measurements and two-side power matching. Experimental results testify the feasibility of the proposed method. These findings suggest that the proposed method is much potential to develop strongly self-adaptive WPT systems with CMR.

Selection of antigenic markers on a GFP-Ckappa fusion scaffold with high sensitivity by eukaryotic ribosome display.

Ribosome display is a cell-free system permitting gene selection through the physical association of genetic material (mRNA) and its phenotypic (protein) product. While often used to select single-chain antibodies from large libraries by panning against immobilized antigens, we have adapted ribosome display for use in the 'reverse' format in order to select high affinity antigenic determinants against solid-phase antibody. To create an antigenic scaffold, DNA encoding green fluorescent protein (GFP) was fused to a light chain constant domain (Ckappa) with stop codon deleted, and with 5' signals (T7 promoter, Kozak) enabling coupled transcription/translation in a eukaryotic cell-free system. Epitopes on either GFP (5') or Ckappa (3') were selected by anti-GFP or anti-Ckappa antibodies, respectively, coupled to magnetic beads. After selection, mRNA was amplified directly from protein-ribosome-mRNA (PRM) complexes by in situ PCR followed by internal amplification and reassembly PCR. As little as 10fg of the 1kb DNA construct, i.e. approximately 7500 molecules, could be recovered following a single round of interaction with solid-phase anti-GFP antibody. This platform is highly specific and sensitive for the antigen-antibody interaction and may permit selection and reshaping of high affinity antigenic variants of scaffold proteins.

Cytotoxic T-cells specific for natural IgE peptides downregulate IgE production.

Immunoglobulin E (IgE) plays a central role in IgE-mediated immediate type hypersensitivity. Since production of IgE depends on Th2, efforts to block IgE production and control allergic reactions include tolerization of Th2 or deviating development of Th2. We hypothesized that cytotoxic T lymphocytes targeting natural IgE peptides/MHC I complexes can eliminate IgE-producing cells and inhibit centrally IgE production. CTL to self-IgE peptides were elicited in mice immunized with nonameric p109-117, p113-121, and p103-141 (CHepsilon2 domain), which encompass both peptides with an OVA helper peptide (OVAp restricted for H-2d/b) in liposomes and presented by dendritic cells (DC). CTL from BALB/c lysed IgE peptide-pulsed P815 target as well as IgE-producing 26.82 hybridomas (H-2d). Natural tolerance to self-IgE peptides was tested in IgE sufficient (IgE +/+) as well as IgE-deficient (IgE -/-) 129/SvEv mice (H-2b). Comparable magnitude of CTL responses was observed in both strains immunized with p109-117 or p103-141 concomitantly with CD4 T-cell costimulation. CTL from 129/SvEv lysed not only IgE peptide-pulsed EL-4 but also IgE-producing B4 hybridomas (H-2b). This observation strongly suggests a correspondence of epitope of immunogenic peptide to that of physiologically processed IgE peptides presented on IgE-producing cells. Moreover, CTL were generated in 129/SvEv, immunized with the recombinant antigenized antibody in liposomes encompassing p107-123, p109-117, and p113-121 expressed in CDR3 of VH62/human gamma1. Polyclonal IgE production was inhibited by coincubation with MHC I-restricted CTL in vitro. Furthermore, antigen-specific IgE responses were inhibited in mice, immunized with p109-117 and p103-141 while IgG responses were not suppressed. Since IgE peptide sequences of CHepsilon2 are ubiquitous to all murine IgE heavy chain, peptides made as such can serve as a universal IgE vaccine to prevent allergy for a myriad of allergens in rodents. This observation suggests that similar human IgE peptides should be identified and employed to downregulate human IgE production.