Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does ...not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.
Site-specific conjugation of small molecules to antibodies represents an attractive goal for the development of more homogeneous targeted therapies and diagnostics. Most site-specific conjugation ...strategies require modification or removal of antibody glycans or interchain disulfide bonds or engineering of an antibody mutant that bears a reactive handle. While such methods are effective, they complicate the process of preparing antibody conjugates and can negatively impact biological activity. Herein we report the development and detailed characterization of a robust photoaffinity cross-linking method for site-specific conjugation to fully glycosylated wild-type antibodies. The method employs a benzoylphenylalanine (Bpa) mutant of a previously described 13-residue peptide derived from phage display to bind tightly to the Fc domain; upon UV irradiation, the Bpa residue forms a diradical that reacts with the bound antibody. After the initial discovery of an effective Bpa mutant peptide and optimization of the reaction conditions to enable efficient conjugation without concomitant UV-induced photodamage of the antibody, we assessed the scope of the photoconjugation reaction across different human and nonhuman antibodies and antibody mutants. Next, the specific site of conjugation on a human antibody was characterized in detail by mass spectrometry experiments and at atomic resolution by X-ray crystallography. Finally, we adapted the photoconjugation method to attach a cytotoxic payload site-specifically to a wild-type antibody and showed that the resulting conjugate is both stable in plasma and as potent as a conventional antibody–drug conjugate in cells, portending well for future biological applications.
Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody–drug conjugates (ADCs), and many examples are currently in clinical development. In order to ...further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules were modified by the systematic introduction of acidic and basic moieties into their chemical structures. The impact of these changes on DNA binding, cell membrane permeability, and in vitro antiproliferation potency was, respectively, determined using a DNA alkylation assay, PAMPA assessments, and cell-based cytotoxicity measurements conducted with a variety of cancer lines. The modified PBD-dimer compounds were subsequently incorporated into CD22-targeting ADCs, and these entities were profiled in a variety of in vitro and in vivo experiments. The introduction of a strongly basic moiety into the PBD-dimer scaffold afforded a conjugate with dramatically worsened mouse tolerability properties relative to ADCs derived from related payloads, which lacked the basic group.
One challenging aspect in the clinical development of molecularly targeted therapies, which represent a new and promising approach to treating cancers, has been the identification of a biologically ...active dose rather than a maximum tolerated dose. The goal of the present study was to identify a pharmacokinetic/pharmacodynamic relationship in preclinical models that could be used to help guide selection of a clinical dose. SU11248, a novel small molecule receptor tyrosine kinase inhibitor with direct antitumor as well as antiangiogenic activity via targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), KIT, and FLT3 receptor tyrosine kinases, was used as the pharmacological agent in these studies. In mouse xenograft models, SU11248 exhibited broad and potent antitumor activity causing regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. To predict the target SU11248 exposure required to achieve antitumor activity in mouse xenograft models, we directly measured target phosphorylation in tumor xenografts before and after SU11248 treatment and correlated this with plasma inhibitor levels. In target modulation studies in vivo, SU11248 selectively inhibited Flk-1/KDR (VEGF receptor 2) and PDGF receptor beta phosphorylation (in a time- and dose-dependent manner) when plasma concentrations of inhibitor reached or exceeded 50-100 ng/ml. Similar results were obtained in a functional assay of VEGF-induced vascular permeability in vivo. Constant inhibition of VEGFR2 and PDGF receptor beta phosphorylation was not required for efficacy; at highly efficacious doses, inhibition was sustained for 12 h of a 24-h dosing interval. The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.
This paper describes a promising photoelectrochemical electrode based on a flower‐like Cu2In2ZnS5 structure composed of nanosheets and its use as a photoelectrode for photoelectrochemical (PEC) water ...splitting for the first time. The detailed growth of Cu2In2ZnS5 was discussed. The morphology and microstructure were characterized in detail. PEC measurements showed that on the basis of the optimal hydrothermal time, flower‐like Cu2In2ZnS5 exhibited high photoelectrochemical activity, as the photocurrent density reached up to 2.00 mA cm−2. The remarkable PEC performance stems from crucial factors, including improved light absorption, an ideal band gap value, decoupling of the directions of light absorption and charge‐carrier collection, and large surface area. Our results indicate that the flower‐like Cu2In2ZnS5 structure composed of nanosheets has enormous potential in PEC water splitting.
Time to split up: A flower‐like Cu2In2ZnS5 structure composed of nanosheets is prepared and used as a photoelectrode for photoelectrochemical water splitting. Cu2In2ZnS5 reaches a photocurrent density up to 2.00 mA cm−2; this remarkable activity is a result of improved light absorption, an ideal band gap value, decoupling of the directions of light absorption and charge‐carrier collection, and a large surface area.
Purpose
The purpose of this paper is to investigate problems in performing stable lane changes and to find a solution to reduce energy consumption of autonomous electric vehicles.
...Design/methodology/approach
An optimization algorithm, model predictive control (MPC) and Karush–Kuhn–Tucker (KKT) conditions are adopted to resolve the problems of obtaining optimal lane time, tracking dynamic reference and energy-efficient allocation. In this paper, the dynamic constraints of vehicles during lane change are first established based on the longitudinal and lateral force coupling characteristics and the nominal reference trajectory. Then, by optimizing the lane change time, the yaw rate and lateral acceleration that connect with the lane change time are limed. Furthermore, to assure the dynamic properties of autonomous vehicles, the real system inputs under the restraints are obtained by using the MPC method. Based on the gained inputs and the efficient map of brushless direct-current in-wheel motors (BLDC IWMs), the nonlinear cost function which combines vehicle dynamic and energy consumption is given and the KKT-based method is adopted.
Findings
The effectiveness of the proposed control system is verified by numerical simulations. Consequently, the proposed control system can successfully achieve stable trajectory planning, which means that the yaw rate and longitudinal and lateral acceleration of vehicle are within stability boundaries, which accomplishes accurate tracking control and decreases obvious energy consumption.
Originality/value
This paper proposes a solution to simultaneously satisfy stable lane change maneuvering and reduction of energy consumption for autonomous electric vehicles. Different from previous path planning researches in which only the geometric constraints are involved, this paper considers vehicle dynamics, and stability boundaries are established in path planning to ensure the feasibility of the generated reference path.
Recent achievements in the development of multitargeted molecular inhibitors necessitate a better understanding of the contribution of activity against individual targets to their efficacy. SU11248, ...a small-molecule inhibitor targeting class III/V receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors, KIT and FLT3, exhibits direct effects on cancer cells as well as antiangiogenic activity. Here, we investigated the contributions of inhibiting individual SU11248 target receptors to its overall antitumor efficacy in tumor models representing diverse signaling paradigms. Consistent with previous results, SU11248 was highly efficacious (frequently cytoreductive) in all models tested. To elucidate the specific contributions of inhibition of PDGF and VEGF receptors to the in vivo efficacy of SU11248, we employed two selective inhibitors, SU10944 (VEGF receptor inhibitor) and Gleevec (PDGF receptor inhibitor). SU10944 alone induced a tumor growth delay in all models evaluated, consistent with a primarily antiangiogenic mode of action. In contrast, Gleevec resulted in modest growth inhibition in tumor models in which the cancer cells expressed its targets (PDGFRbeta and KIT), but was not efficacious against tumors not driven by these target receptor tyrosine kinases. Strikingly, in all but one tumor model evaluated, the antitumor efficacy of SU10944 combined with Gleevec was similar to that of single-agent SU11248, and was greatly superior to that of each compound alone, indicating that the antitumor potency of SU11248 in these models stems from combined inhibition of both PDGF and VEGF receptors. The one exception was a model driven by an activated mutant of FLT3, in which the activity of SU11248, which targets FLT3, was greater than that of SU10944 plus Gleevec. Moreover, SU10944 combined with Gleevec inhibited tumor neoangiogenesis to an extent comparable to that of SU11248. Thus, the potent efficacy of SU11248 in models representing diverse signaling paradigms results from simultaneous inhibition of individual target receptors expressed both in cancer cells and in the tumor neovasculature, supporting the hypothesis that multitargeted inhibitors have the cumulative antitumor efficacy of combined single-target inhibitors.
Reducing the core loss of amorphous cores for distribution transformers Deren Li, Liang Zhang, Guangmin Li, Zhichao Lu, Shaoxiong Zhou China Iron & Steel Research Institute Group, Advanced Technology and Materials Co., Ltd., No. 76, Xueyuan Nan Rd., Haidian District, Beijing 100081, China
Progress in natural science,
06/2012, Letnik:
22, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Although amorphous alloy ribbons have lower core loss, serious loss deterioration occurs in amorphous cores constructed from amorphous alloy ribbon for distribution transformer. In the present study, ...the loss deterioration mechanism and influencing factors of amorphous cores for distribution transformers were investigated. The influence of distributed gaps on core loss of transformer core was calculated by simulation software and validated by experiments. The boron fluctuation of amorphous alloy ribbons affects the annealing temperature of amorphous transformer cores. A superior core annealing technique with annealing parameters was developed, and appreciable decrease in core loss was obtained.
This paper addresses the challenge of significant interference caused by direct sunlight, which adversely affects the orientation accuracy of underwater imaging polarization sensors (IPS). A novel ...underwater polarization orientation method is proposed based on direct sunlight compensation. Firstly, based on the polarization transmission model at the water-air interface, the interference mechanism of the underwater direct sunlight polarization detection model was analyzed. The underwater IPS detection model based on direct sunlight compensation is constructed, which uses the weight coefficient of underwater direct sunlight to compensate for the interference on the polarization channel and improve the accuracy of underwater polarization detection models. Furthermore, the analytical solution method for the polarization state information of underwater IPS is proposed, employing the augmented Stokes vectors to construct a linear equation for solving the weight coefficients of direct sunlight and improving the computational efficiency. Finally, an underwater polarization orientation experimental platform is established, and both simulation and actual underwater experiments are conducted. Compared with the traditional methods, the proposed method reduces heading error by an average of 92.53% at different solar altitudes.
With the advantages of anti-interference and no accumulated error, bionic polarization heading measurement has important military significance and research value for autonomous navigation. However, ...the heading robustness is seriously affected by the accuracy of the skylight polarization model and the existing methods all use the Rayleigh scattering model without considering atmospheric depolarization. Therefore, this article proposed an innovative method of polarization heading measurement based on the Berry model to consider the influence of depolarization neutral points. And this model is improved by controlling the neutral points with correction coefficients to realize high-robustness heading measurement. On this basis, the improved Berry model is further used to calibrate the sensor parameters outdoors, which separates the skylight polarization model error from the sensor error without expensive instruments and complicated processes and improves the heading measurement accuracy. In the experiments with changing solar altitude, the average heading error STD after field calibration is 20.86% lower than that of the Berry model and 92.85% lower than that of the Rayleigh model, which shows great advancement in actual measurements.
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