The prosperity of the biotherapeutics market reflects the feasibility and effectiveness of therapeutic antibodies for the treatment of cancers, inflammatory disorders, and refractory infections. As drawbacks emerge in clinical trials and practice, such as impeded binding, reduced effector functions, and frequent adverse reactions, modifications of therapeutic antibodies are unprecedently burgeoning in research and development (R&D). These modifications include: ① modified glycosylation; ② fragment of crystallizable domain (Fc) amino acid alterations; ③ cross-isotype or cross-subclass exchanges; ④ antibody–drug conjugates (ADCs); ⑤ single chain of variable region fragment (scFv) for chimeric antigen receptor T (CAR-T) cells; and ⑥ bispecific antibodies (bsAbs) in order to promote binding affinity, half-life in circulation, effectiveness toward target cells and, ultimately, to achieve overall improved efficacy. While many achievements have been made around the world in the past decades, China has been playing an active role in this realm, with its great demand for biotherapeutics with R&D potential. This review recapitulates the international progress that has been achieved with modified therapeutic antibodies, and then focuses on that of China in an independent section.
In analyses of protein families that may serve as drug targets, membrane-associated G-protein-coupled receptors (GPCRs) dominate, followed by ion channels, transporters, and—to a lesser extent—membrane-bound enzymes. However, various challenges put such membrane proteins among key groups of underutilized opportunities for the application of therapeutic antibodies. Antibodies hold the promise of exquisite specificity, as they are able to target even specific conformations of a particular membrane protein, as well as adaptability through engineering into various antibody formats. However, the ease of raising and isolating specific, effective antibodies targeting membrane proteins depends on many factors. In particular, the generation of specific antibodies is easier when targeting larger, simpler, extracellular domains with greater uniqueness of amino acid sequence. The rareness of such ideal conditions is illustrated by the limited number of approved biologics for targeting GPCRs and other complex membrane proteins. Challenges in developing antibodies to complex membrane proteins such as GPCRs, ion channels, transporters, and membrane-bound enzymes can be addressed by the design of the antigen, antibody-generation strategies, lead optimization technologies, and antibody modalities. A better understanding of the membrane proteins being targeted would facilitate mechanism-based drug discovery. This review describes the advantages and challenges of targeting complex membrane proteins with antibodies and discusses the preparation of membrane protein antigens and antibody generation, illustrated by select examples of success.
Allergic disease is one of the most common chronic diseases, which can affect both children and adults, be often caused by allergen-induced unfavorable immune responses, and initiate various symptoms in different organs, including up-/low-airways and skin, such as asthma, atopic dermatitis, and rhinosinusitis. With increasing prevalence of allergic disease worldwide and their impact on the quality of life, new biological therapeutic approaches for these disorders become hot areas of intensive research. Multiple factors are involved and play important role in the pathogenesis of allergic disease, which can promote or trigger T helper 2 (Th2)-type immune responses, leading to production of the type 2 cytokines and immunoglobulin E (IgE)，the two critical events in the allergic diseases. Using monoclonal antibodies to target these molecules, therefore, might provide possible benefits for the patients suffered from these diseases. Apart of those having approved biologics for allergic diseases, some potential targets such as epithelial-derived alarmins thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33) have been also described and proposed to develop monoclonal antibodies against either these cytokines, their receptors, or both. These new and potential targets have substantially enriched the therapeutic opportunities in the field of allergic diseases. The present review aims to briefly outline the role of monoclonal antibodies targeting the cytokines and immunoglobulin involved in the development of allergic diseases, and to discuss the clinical effects of these antibodies.
Immunotherapy with anti-programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) monoclonal antibodies has become routine in the treatment of many kinds of human cancers, such as lung cancer, intestinal cancer, and melanoma. The PD-1/PD-L1 pathway inhibits T cell activation in the micro-environment, making it an attractive target against cancer. Wild-type (WT) PD-1 ectodomain has been shown to have difficulty blocking PD-1/PD-L1 mixture formation due to its low affinity. The present work uses three-dimensional (3D) crystal complex structures to analyze the interaction by which PD-1 binds to PD-L1 or PD-L2. It also reports on a theoretical study of the binding mode between PD-1 and its clinical antibody Opdivo. Based on the theoretical binding analysis of PD-1 and its ligands (i.e., PD-L1 and PD-L2) or antibody (Opdivo), a small-content, epitope-oriented mammalian cell library was established for PD-1. After three rounds of cell sorting, the decoy PD-1 mutant 463, which presented a higher affinity than WT PD-1 to the PD-L1 (the affinity has increased by almost three orders of magnitude) was screened out. It exhibited an inhibitory effect against PD-1 to prevent it from forming mixtures with PD-L1, which was similar to the effect of the commercial anti-PD-L1 antibody atezolizumab (ATE). The median effective concentration (EC50) value of the decoy mutant was 0.031 μg·mL−1 in comparison with 0.063 μg·mL−1 for ATE; both values were much lower than that of WT PD-1, at 2.571 μg·mL−1. The 463 decoy mutant reversed the inhibitory function of PD-1 in T cell activation; furthermore, 10 mg·kg−1 of 463 inhibited about 75% of tumor growth in vivo in a MC38 transgenic xenograft mice model, which was similar to the activity of ATE. More interestingly, an even lower dose of 463 (2 mg·kg−1) showed a better effect than 10 mg·kg−1 of WT PD-1. This work offers the decoy 463 with an improved curative effect, which holds potential to become a good option against PD-1/PD-L1-related cancers.
Fully human antibodies have minimal immunogenicity and safety profiles. At present, most potential antibody drugs in clinical trials are humanized or fully human. Human antibodies are mostly generated using the phage display method (in vitro) or by transgenic mice (in vivo); other methods include B lymphocyte immortalization, human–human hybridoma, and single-cell polymerase chain reaction. Here, we describe a structure-based computer-aided de novo design technology for human antibody generation. Based on the complex structure of human epidermal growth factor receptor 2 (HER2)/Herceptin, we first designed six short peptides targeting the potential epitope of HER2 recognized by Herceptin. Next, these peptides were set as complementarity determining regions in a suitable immunoglobulin frame, giving birth to a novel anti-HER2 antibody named “HF,” which possessed higher affinity and more effective anti-tumor activity than Herceptin. Our work offers a useful tool for the quick design and selection of novel human antibodies for basic mechanical research as well as for imaging and clinical applications in immune-related diseases, such as cancer and infectious diseases.
Lung cancer is a leading cause of cancer-related death worldwide, with a very poor overall five-year survival rate. The intrinsic limitations associated with the conventional diagnosis and therapeutic strategies used for lung cancer have motivated the development of nanotechnology and nanomedicine approaches, in order to improve early diagnosis rate and develop more effective and safer therapeutic options for lung cancer. Cancer nanomedicines aim to individualize drug delivery, diagnosis, and therapy by tailoring them to each patient's unique physiology and pathological features—on both the genomic and proteomic levels—and have attracted widespread attention in this field. Despite the successful application of nanomedicine techniques in lung cancer research, the clinical translation of nanomedicine approaches remains challenging due to the limited understanding of the interactions that occur between nanotechnology and biology, and the challenges posed by the toxicology, pharmacology, immunology, and large-scale manufacturing of nanoparticles. In this review, we highlight the progress and opportunities associated with nanomedicine use for lung cancer treatment and discuss the prospects of this field, together with the challenges associated with clinical translation.
In this study, normal values of semen analysis were set for a general infertile population of couples among which most women had normal ovulation. The predictive capacity values of sperm quality, including concentration, motile count, progressive motile count, and morphology, are unclear for women with polycystic ovary syndrome (PCOS). A secondary analysis was conducted based on a randomized controlled trial investigating infertility among women with PCOS experiencing ovulatory disorder between 2011 and 2016 in China. A total of 1000 women received ovulation induction (acupuncture and clomiphene). We randomized the women with PCOS in 27 hospitals in China who received one of four interventions (acupuncture plus clomiphene, sham acupuncture plus clomiphene, acupuncture plus placebo, or sham acupuncture plus placebo). Semen analysis was performed for every male partner according to the World Health Organization (WHO) criteria. The outcomes included conception, clinical pregnancy, and live birth. Logistic regression was used to evaluate the predictive value of semen analysis among ovulatory women for conception, clinical pregnancy, and live birth. Among the 1000 couples, the number of couples who attained ovulation, conception, clinical pregnancy, and live birth were 780, 320, 235, and 205, respectively. Semen volume and motility were applied and used as prediction parameters for conception (area under the curve (AUC) of 0.62 (95% confidence interval (CI), 0.55–0.69)), clinical pregnancy (AUC of 0.67 (95%CI: 0.61–0.73)), and live birth (AUC of 0.57 (95%CI: 0.50–0.64)). No poor calibration was shown for these models in Hosmer–Lemeshow tests. The predictive capacity of semen analysis for treatment outcome in PCOS women with PCOS experiencing with ovulatory dysfunction is limited.
The molecular network features of spinal cord development that are integral to tissue engineering remain poorly understood in placental mammals, especially in terms of their relationships with vital biological processes such as regeneration. Here, using a large-scale temporal transcriptomic analysis of rat spinal cord from the embryonic stage to adulthood, we show that fluctuating RNA expression levels reflect highly active transcriptional regulation, which may initiate spinal cord patterning. We also demonstrate that microRNAs (miRNAs) and transcriptional factors exhibit a mosaic profile based on their expression patterns, while differential alternative splicing events reveal that alternative splicing may be a driving force for the development of the node of Ranvier. Our study also supports the existence of a negative correlation between innate immunity and intrinsic growth capacity. Epigenetic modifications appear to perform their respective regulatory functions at different stages of development, while guanine nucleotide-binding protein (G protein)-coupled receptors (including olfactory receptors (ORs)) may perform pleiotropic roles in axonal growth. This study provides a valuable resource for investigating spinal cord development and complements the increasing number of single-cell datasets. These findings also provide a genetic basis for the development of novel tissue engineering strategies.
Pollution involving pharmaceutical components in bodies of water is an increasingly serious environmental issue. Plasma discharge for the degradation of antibiotics is an emerging technology that may be relevant toward addressing this issue. In this work, a plasma-assisted rotating disk reactor (plasma-RDR) and a photocatalyst—namely, titanium dioxide (TiO2)—were coupled for the treatment of metronidazole (MNZ). Discharge uniformity was improved by the use of a rotating electrode in the plasma-RDR, which contributed to the utilization of ultraviolet (UV) light radiation in the presence of TiO2. The experimental results showed that the degradation efficiency of MNZ and the concentration of generated hydroxyl radicals respectively increased by 41% and 2.954 mg·L−1 as the rotational speed increased from 0 to 500 r·min−1. The synergistic effect of plasma-RDR plus TiO2 on the generation of hydroxyl radicals was evaluated. Major intermediate products were identified using three-dimensional (3D) excitation emission fluorescence matrices (EEFMs) and liquid chromatography–mass spectrometry (LC-MS), and a possible degradation pathway is proposed herein. This plasma-catalytic process has bright prospects in the field of antibiotics degradation.
China has become the world's largest producer and consumer of energy, and ranks first in its wind and solar power installation capacity. However, increasingly serious wind and solar curtailment in China has significantly hindered the development and utilization of renewable energy. To address problems in the consumption of renewable energy, this paper analyzes four key factors affecting the capacity of power generated from renewable energy sources: power balance, power regulation performance, transmission capacity, and load level. Focusing on these bottlenecks, we propose seven solutions: centralized and distributed development of renewable energy, improving the peak-load regulation flexibility of thermal power, increasing the proportion of gas turbines and pumped-hydropower storage, construction of transmission channels and a flexible smart grid developing demand response and virtual power plants, adopting new energy active support and energy storage, and establishing appropriate policies and market mechanisms. The Chinese government and energy authorities have issued a series of policies and measures, and in the past three years, China has had remarkable achievements in the adoption of renewable energy. The rate of idle wind capacity decreased from 17% in 2016 to 7% in 2018, and that of solar decreased from 10% in 2016 to 3% in 2018.
Simple and efficient nanofabrication technology with low cost and high flexibility is indispensable for fundamental nanoscale research and prototyping. Lithography in the near field using the surface plasmon polariton (i.e., plasmonic lithography) provides a promising solution. The system with high stiffness passive nanogap control strategy on a high-speed rotating substrate is one of the most attractive high-throughput methods. However, a smaller and steadier plasmonic nanogap, new scheme of plasmonic lens, and parallel processing should be explored to achieve a new generation high resolution and reliable efficient nanofabrication. Herein, a parallel plasmonic direct-writing nanolithography system is established in which a novel plasmonic flying head is systematically designed to achieve around 15 nm minimum flying-height with high parallelism at the rotating speed of 8–18 m•s−1. A multi-stage metasurface-based polarization insensitive plasmonic lens is proposed to couple more power and realize a more confined spot compared with conventional plasmonic lenses. Parallel lithography of the nanostructures with the smallest ( around 26 nm) linewidth is obtained with the prototyping system. The proposed system holds great potential for high- freedom nanofabrication with low cost, such as planar optical elements and nano-electromechanical systems.
The construction of a lunar base and habitation on the Moon has always been on researchers' minds. Building materials used in in situ lunar resources are of great significance for saving expensive space freight. In this study, a new type of lunar soil simulant named Beihang (BH)-1 was developed. The chemical mineral composition and microstructure of BH-1 closely resemble those of real lunar soil, as verified by X-ray fluorescence spectroscopy (XRF), X-ray diffraction (XRD), scanning electron microscopy (SEM), and reflectance spectra. This research also synthesized a geopolymer based on BH-1 cured at simulated lunar atmospheric conditions. We also investigated the effect of supplementing aluminum (Al) sources on the enhancement of geopolymer strength based on BH-1. The rheological behavior of alkali-activated BH-1 pastes was determined for workability. XRF, XRD, Fourier transform infrared spectroscopy, SEM coupled with energy dispersive spectroscopy, and 27Al magic angle spinning-nuclear magnetic resonance were used to characterize resulting geopolymers. Rheological test findings showed that the rheology of BH-1 pastes fits the Herschel–Bulkley model, and they behaved like a shear-thinning fluid. The results showed that the 28-day compressive strength of the BH-1 geopolymer was improved by up to 100.8%. Meanwhile, the weight of additives required to produce per unit strength decreased, significantly reducing the mass of materials transported from the Earth for the construction of lunar infrastructure and saving space transportation costs. Microscopic analyses showed that the mechanism to improve the mechanical properties of the BH-1 geopolymer by adding an additional Al source enhances the replacement of silicon atoms by Al atoms in the silicon–oxygen group and generates a more complete and dense amorphous gel structure.
Tephritid flies threaten the production of fruits around the world. In the Americas, populations of the genus Anastrepha are monitored with trapping networks as part of pest management programs. Here, we report the formulation of male Anastrepha suspensa (Loew) pheromones, (±)-anastrephin and (±)-epianastrephin, into a poly(vinyl chloride) (PVC) polymer-based lure ready for trap deployment. The PVC polymer disks (100 mg) contain 10% by weight of (±)-epianastrephin and (±)-anastrephin in a naturally occurring 7:3 diastereomeric ratio, respectively. Emission of the pheromones from the disks into an airstream was evaluated as a function of abiotic environmental parameters, absolute humidity, and temperature. Kinetic data supports a diffusion-controlled mechanism of release from the matrix with first-order rate constants that decreased about 10-fold as the temperature was lowered from 30 to 15 °C. As such, the emission of volatile pheromones from the disks is suitable to last for several weeks in the field. This kinetic approach, which can be easily extended to the diffusion-controlled release of other attractants from polymeric matrices, yields laboratory predictions of the potential for environmental loss prior to conducting field bioassays.