Accelerating the speed of innovative anti-tumor drugs to first-in-human trials incorporating key de-risk strategies.

Pharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool can be used to produce materials for the toxicology (Tox) study, reducing time to the clinic by 4-5 months. During the coronavirus disease 2019 (COVID-19) pandemic, the anti-COVID drugs timeline from DNA transfection to the clinical stage was decreased to 6 months using a stable pool to generate a clinical drug substrate (DS) with limited stability, virus clearance, and Tox study package. However, a lean chemistry, manufacturing, and controls (CMC) package raises safety and comparability risks and may leave extra work in the late-stage development and commercialization phase. In addition, whether these accelerated COVID-19 drug development strategies can be applied to non-COVID projects and established as a standard practice in biologics development is uncertain. Here, we present a case study of a novel anti-tumor drug in which application of "fast-to-FIH" approaches in combination with BeiGene's de-risk strategy achieved successful delivery of a complete CMC package within 10 months. A comprehensive comparability study demonstrated that the DS generated from a stable pool and a single-cell-derived master cell bank were highly comparable with regards to process performance, product quality, and potency. This accomplishment can be a blueprint for non-COVID drug programs that approach the pace of drug development during the pandemic, with no adverse impact on the safety, quality, and late-stage development of biologics.

SceneHGN: Hierarchical Graph Networks for 3D Indoor Scene Generation With Fine-Grained Geometry.

3D indoor scenes are widely used in computer graphics, with applications ranging from interior design to gaming to virtual and augmented reality. They also contain rich information, including room layout, as well as furniture type, geometry, and placement. High-quality 3D indoor scenes are highly demanded while it requires expertise and is time-consuming to design high-quality 3D indoor scenes manually. Existing research only addresses partial problems: some works learn to generate room layout, and other works focus on generating detailed structure and geometry of individual furniture objects. However, these partial steps are related and should be addressed together for optimal synthesis. We propose SceneHGN, a hierarchical graph network for 3D indoor scenes that takes into account the full hierarchy from the room level to the object level, then finally to the object part level. Therefore for the first time, our method is able to directly generate plausible 3D room content, including furniture objects with fine-grained geometry, and their layout. To address the challenge, we introduce functional regions as intermediate proxies between the room and object levels to make learning more manageable. To ensure plausibility, our graph-based representation incorporates both vertical edges connecting child nodes with parent nodes from different levels, and horizontal edges encoding relationships between nodes at the same level. Our generation network is a conditional recursive neural network (RvNN) based variational autoencoder (VAE) that learns to generate detailed content with fine-grained geometry for a room, given the room boundary as the condition. Extensive experiments demonstrate that our method produces superior generation results, even when comparing results of partial steps with alternative methods that can only achieve these. We also demonstrate that our method is effective for various applications such as part-level room editing, room interpolation, and room generation by arbitrary room boundaries.

Isomer differentiation through supramolecular self-assembly in microdroplets of milliseconds life-time.

Supramolecular recognition of thymine (or its analogs) with various central cations can form magic number clusters. Dual nano-ESI via theta tip emitters was used to on-line synthesize clusters. Even thermodynamically unstable clusters can be detected by MS thanks to the very short life-time (∼ms) of the generated microdroplets. By recording characteristic cluster distributions, isomers can be clearly differentiated in a novel "bottom-up" way. Theoretical calculations were performed to explain the MS results.

Highly sensitive and specific detection of histamine via the formation of a self-assembled magic number cluster with thymine by mass spectrometry.

A novel method for the detection of histamine (HIM) via the formation of a self-assembled magic number cluster with thymine (T) by electrospray ionization tandem mass spectrometry (ESI-MS/MS) is described. The formation of the magic number cluster [T17 + HIM + 2H](2+) shifts the MS signal of histamine to the interference-free higher mass range and the signal intensity is increased by four orders of magnitude. In addition, the formation of [T17 + HIM + 2H](2+) is highly specific to histamine compared with its metabolite and other similar biogenic amines, which may be attributed to both of its amino and imidazole groups. The linear dynamic range of the method is in the range of 1 nM-20 µM, and the limit of detection can be as low as 0.1 nM. The feasibility of this method is further demonstrated by the quantitative analysis of histamine in a red wine sample. Since little sample preparation or separation is required before the analysis, this method provides a rapid new way for the sensitive and specific detection of histamine by MS.

Protonated primary amines induced thymine quintets studied by electrospray ionization mass spectrometry and density functional theory calculations.

As the novel magic number clusters of nucleobases, the thymine quintets induced by ammonium ion (NH4(+)), and particularly by its derivatives such as protonated alkyl amines and protonated aryl amines, have been studied by electrospray ionization mass spectrometry (ESI-MS) and density functional theory (DFT) calculations. The DFT-optimized geometry of NH4(+) induced thymine quintet ([T5 + NH4](+)) reveals some new features including three additional hydrogen bonds between NH4(+) and its surrounding thymine molecules when compared with that of the alkali metal ions induced thymine quintets. In addition, the fourth hydrogen atom of NH4(+) is sticking out the assembly, and, thus, it might be replaced by an organic group R to form the protonated primary amine induced thymine quintet ([T5 + R - NH3](+)), a hypothesis that has been confirmed by both DFT calculations and ESI-MS experiments. Furthermore, the relative abilities of the different protonated primary amines for inducing the thymine quintets are investigated by ESI-MS competition experiments, and the results have shown a clear trend of stronger ability as the alkyl chain gets longer or as the aryl ring gets larger for the alkyl amines or the aryl amines. Two basic influence factors are consequently identified: one is the ability of the alkyl amine to accept proton, another is the π-π stacking interaction between the aryl ring and the π-surface of the thymine molecule(s), whose explanations are strongly supported by multiple types of thermochemical data, various control experiments and DFT calculations.

Signal enhancement of carboxylic acids by inclusion with ß-cyclodextrin in negative high-voltage-assisted laser desorption ionization mass spectrometry.

RATIONALE: It is difficult to directly analyze carboxylic acids in complex mixtures by ambient high-voltage-assisted laser desorption ionization mass spectrometry (HALDI-MS) in negative ion mode due to the low ionization efficiency of carboxylic acids. METHODS: A method for the rapid detection of carboxylic acids in negative HALDI-MS has been developed based on their inclusion with ß-cyclodextrin (ß-CD). RESULTS: The negative HALDI-MS signal-to-noise ratios (S/Ns) of aliphatic, aromatic and hetero atom-containing carboxylic acids can all be significantly improved by forming 1:1 complexes with ß-CD. These complexes are mainly formed by specific inclusion interactions which are verified by their collision-induced dissociation behaviors in comparison with that of their corresponding maltoheptaose complexes. A HALDI-MS/MS method has been successfully developed for the detection of α-lipoic acid in complex cosmetics and ibuprofen in a viscous drug suspension. CONCLUSIONS: The negative HALDI-MS S/Ns of carboxylic acids can be improved up to 30 times via forming non-covalent complexes with ß-CD. The developed method shows the advantages of being rapid and simple, and is promising for rapid detection of active ingredients in complex samples or fast screening of drugs and cosmetics.

Laser desorption dual spray post-ionization mass spectrometry for direct analysis of samples via two informative channels.

A laser desorption dual spray post-ionization mass spectrometry method is described, and its usefulness is demonstrated with the examples of selective detection of food components, manipulation of protein charge state distribution and investigation on the formation of magic number clusters. The method is carried out by adopting two spray emitters for post-ionization of analytes desorbed by a pulsed infrared laser. Various components in a complex sample or distinct behavior of an analyte in two different spray reagents can be rapidly probed by the method quasi-simultaneously, highlighting the potential applications of this method for protein characterization, reaction study and food analysis.

Unexpected complexation reaction during analysis of proteins using laser desorption spray post-ionization mass spectrometry.

We describe complexation reactions of insulin and other proteins with metal ions generated from the substrate surface by laser irradiation in laser desorption spray post-ionization mass spectrometry (LDSPI-MS). This particular type of complexation reaction in LDSPI-MS was investigated for the first time, which indicated that the mechanistic process of LDSPI-MS might be much more complicated than that proposed before for similar methods.