scholarly journals Dissecting the impact of target-binding kinetics of protein binders on tumor localization

iScience ◽  
2021 ◽  
Vol 24 (2) ◽  
pp. 102104
Author(s):  
Yunjin Song ◽  
Hoibin Jeong ◽  
Song-Rae Kim ◽  
Yiseul Ryu ◽  
Jonghwi Baek ◽  
...  
Keyword(s):  
Binding Kinetics ◽  
Tumor Localization ◽  
Protein Binders ◽  
Target Binding ◽  
The Impact ◽  
Kinetics Of

scholarly journals Molecular Interaction Characterization Strategies for the Development of New Biotherapeutic Antibody Modalities

Antibodies ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 7
Author(s):  
Xiangdan Wang ◽  
Minh Michael Phan ◽  
Ji Li ◽  
Herman Gill ◽  
Simon Williams ◽  
...  
Keyword(s):  
Molecular Interaction ◽  
Binding Kinetics ◽  
Therapeutic Development ◽  
Dosing Regimens ◽  
Fit For Purpose ◽  
Target Binding ◽  
The Impact ◽  
First Time

The characterization of target binding interactions is critical at each stage of antibody therapeutic development. During early development, it is important to design fit-for-purpose in vitro molecular interaction characterization (MIC) assays that accurately determine the binding kinetics and the affinity of therapeutic antibodies for their targets. Such information enables PK/PD (pharmacokinetics/pharmacodynamics) modeling, estimation of dosing regimens, and assessment of potency. While binding kinetics and affinities seem to be readily obtained, there is little discussion in the literature on how the information should be generated and used in a systematic manner along with other approaches to enable key drug development decisions. The introduction of new antibody modalities poses unique challenges to the development of MIC assays and further increases the need to discuss the impact of developing context-appropriate MIC assays to enable key decision making for these programs. In this paper, we discuss for the first time the challenges encountered when developing MIC assays supporting new antibody modalities. Additionally, through the presentation of several real case studies, we provide strategies to overcome these challenges to enable investigational new drug (IND) filings.

scholarly journals Impact of real-time shedding on binding kinetics of membrane-remaining L-selectin to PSGL-1

2019 ◽  
Vol 316 (5) ◽  
pp. C678-C689 ◽  
Author(s):  
Shuang Peng ◽  
Shen-Bao Chen ◽  
Lin-Da Li ◽  
Chun-Fang Tong ◽  
Ning Li ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Real Time ◽  
Jurkat Cells ◽  
Binding Kinetics ◽  
Time Dependent ◽  
Intact Cells ◽  
The Impact ◽  
Kinetics Of

L-selectin shedding induced by various cytokines is crucial in activating neutrophils (PMNs) in inflammatory cascade. While the real-time shedding in vivo lasts ~10 min after PMN activation, the impact of time-dependent shedding on binding kinetics of membrane-remaining L-selectins to its ligands is poorly understood at transient or steady state. Here, we developed an in vitro L-selectin shedding dynamics approach, together with competitive assays of cell adhesion, and proposed a theoretical model for quantifying the impact of real-time shedding on the binding kinetics of membrane-remaining L-selectins to P-selectin glycoprotein ligand-1 (PSGL-1). Our data indicated that the extent of L-selectin shedding on PMA activation is higher, but the terminating time is longer for Jurkat cells than those for human PMNs. Meanwhile, fMLF or IL-8 stimulation yields the longer terminating time than that on PMA stimulation but results in a similar shedding extent for PMNs. L-selectin shedding reduces L-selectin-PSGL-1-mediated cell adhesion in three ways: decreasing membrane-anchored L-selectins, increasing soluble L-selectins competitively binding to ligands, and presenting conformational alteration of membrane-remaining L-selectins themselves. Compared with those on intact cells, the binding affinities of membrane-remaining L-selectin-PSGL-1 pairs were all enhanced at initial and lowered at the late shedding phase for both PMN and Jurkat cells even with varied transition time points. The rolling velocities of both PMNs and Jurkat cells were increased following mechanically or biochemically induced shedding of L-selectin under shear flow. These findings help to further our understanding of the function of time-dependent L-selectin shedding during the inflammation cascade.

Binding kinetics of fluorescent bisphosphonates as a tool for monitoring bone dynamics in vivo

2013 ◽  
Author(s):  
Robert Tower ◽  
Graeme Campbell ◽  
Marc Muller ◽  
Olga Will ◽  
Frederieka Grundmann ◽  
...  
Keyword(s):  
Binding Kinetics ◽  
Kinetics Of ◽  
Bone Dynamics

Influence of Brain Gangliosides on the Formation and Properties of Supported Lipid Bilayers for Binding Kinetics Studies

2018 ◽  
Author(s):  
Luke Jordan ◽  
Nathan Wittenberg
Keyword(s):  
Lipid Bilayers ◽  
Binding Kinetics ◽  
Supported Lipid Bilayers ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Supported Lipid Bilayer ◽  
Head Groups ◽  
Lipid Diffusion ◽  
Kinetics Of ◽  
Brain Gangliosides

This is a comprehensive study of the effects of the four major brain gangliosides (GM1, GD1b, GD1a, and GT1b) on the adsorption and rupture of phospholipid vesicles on SiO2 surfaces for the formation of supported lipid bilayer (SLB) membranes. Using quartz crystal microbalance with dissipation monitoring (QCM-D) we show that gangliosides GD1a and GT1b significantly slow the SLB formation process, whereas GM1 and GD1b have smaller effects. This is likely due to the net ganglioside charge as well as the positions of acidic sugar groups on ganglioside glycan head groups. Data is included that shows calcium can accelerate the formation of ganglioside-rich SLBs. Using fluorescence recovery after photobleaching (FRAP) we also show that the presence of gangliosides significantly reduces lipid diffusion coefficients in SLBs in a concentration-dependent manner. Finally, using QCM-D and GD1a-rich SLB membranes we measure the binding kinetics of an anti-GD1a antibody that has similarities to a monoclonal antibody that is a hallmark of a variant of Guillain-Barre syndrome.

scholarly journals CO Binding Kinetics of Human Cytochrome P450 3A4

1995 ◽  
Vol 270 (10) ◽  
pp. 5014-5018 ◽  
Author(s):  
Aditya P. Koley ◽  
Jeroen T. M. Buters ◽  
Richard C. Robinson ◽  
Allen Markowitz ◽  
Fred K. Friedman
Keyword(s):  
Cytochrome P450 ◽  
Binding Kinetics ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome ◽  
Kinetics Of

scholarly journals Ice Coverage Induced by Depositing a Water Drop onto the Supercooled Substrate at Extreme Low Vapor Pressure

Crystals ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 691
Author(s):  
Yugang Zhao ◽  
Zichao Zuo ◽  
Haibo Tang ◽  
Xin Zhang
Keyword(s):  
Vapor Pressure ◽  
Substrate Temperature ◽  
Water Drop ◽  
Industrial Processes ◽  
Aircraft Icing ◽  
Ice Coverage ◽  
Fundamental Understanding ◽  
Order Of Magnitude ◽  
The Impact ◽  
Kinetics Of

Icing/snowing/frosting is ubiquitous in nature and industrial processes, and the accretion of ice mostly leads to catastrophic consequences. The existing understanding of icing is still limited, particularly for aircraft icing, where direct observation of the freezing dynamics is inaccessible. In this work, we investigate experimentally the impact and freezing of a water drop onto the supercooled substrate at extremely low vapor pressure, to mimic an aircraft passing through clouds at a relatively high altitude, engendering icing upon collisions with pendant drops. Special attention is focused on the ice coverage induced by an impinging drop, from the perimeter pointing outward along the radial direction. We observed two freezing regimes: (I) spread-recoil-freeze at the substrate temperature of Ts = −15.4 ± 0.2 °C and (II) spread (incomplete)-freeze at the substrate temperature of Ts = −22.1 ± 0.2 °C. The ice coverage is approximately one order of magnitude larger than the frozen drop itself, and counterintuitively, larger supercooling yields smaller ice coverage in the range of interest. We attribute the variation of ice coverage to the kinetics of vapor diffusion in the two regimes. This fundamental understanding benefits the design of new anti-icing technologies for aircraft.

scholarly journals Morphology and crystallization kinetics of Rubber-modified Nylon 6 Prepared by Anionic In-situ Polymerization

2020 ◽  
Vol 27 (1) ◽  
pp. 204-215
Author(s):  
Hongkai Zhao ◽  
Dengchao Zhang ◽  
Yingshuang Li
Keyword(s):  
Crystallization Kinetics ◽  
In Situ Polymerization ◽  
Good Description ◽  
Nylon 6 ◽  
Avrami Equation ◽  
Infrared Analysis ◽  
Chain Segment ◽  
The Impact ◽  
Kinetics Of

AbstractIn this work, we modified nylon 6 with liquid rubber by in-situ polymerization. The infrared analysis suggested that HDI urea diketone is successfully blocked by caprolactam after grafting on hydroxyl of HTPB, and the rubber-modified nylon copolymer is generated by the anionic polymerization. The impact section analysis indicated the rubber-modified nylon 6 resin exhibited an alpha crystal form.With an increase in the rubber content, nylon 6 was more likely to generate stable α crystal. Avrami equation was a good description of the non-isothermal crystallization kinetics of nylon-6 and rubber-modified nylon-6 resin. Moreover, it is found that the initial crystallization temperature of nylon-6 chain segment decreased due to the flexible rubber chain segment. n value of rubber-modified nylon-6 indicated that its growth was the coexistence of two-dimensional discoid and three-dimensional spherulite growth. Finally, the addition of the rubber accelerated the crystallization rate of nylon 6.

scholarly journals Single entity electrochemistry and the electron transfer kinetics of hydrazine oxidation

Nano Research ◽  
2021 ◽  
Author(s):  
Ruiyang Miao ◽  
Lidong Shao ◽  
Richard G. Compton
Keyword(s):  
Electron Transfer ◽  
Bulk Solution ◽  
Relative Contribution ◽  
Rate Determining Step ◽  
Multistep Process ◽  
Ph Range ◽  
Electro Catalytic Oxidation ◽  
Single Particle Impact ◽  
The Impact ◽  
Kinetics Of

AbstractThe mechanism and kinetics of the electro-catalytic oxidation of hydrazine by graphene oxide platelets randomly decorated with palladium nanoparticles are deduced using single particle impact electrochemical measurements in buffered aqueous solutions across the pH range 2–11. Both hydrazine, N2H4, and protonated hydrazine N2H5+ are shown to be electroactive following Butler-Volmer kinetics, of which the relative contribution is strongly pH-dependent. The negligible interconversion between N2H4 and N2H5+ due to the sufficiently short timescale of the impact voltammetry, allows the analysis of the two electron transfer rates from impact signals thus reflecting the composition of the bulk solution at the pH in question. In this way the rate determining step in the oxidation of each specie is deduced to be a one electron step in which no protons are released and so likely corresponds to the initial formation of a very short-lived radical cation either in solution or adsorbed on the platelet. Overall the work establishes a generic method for the elucidation of the rate determining electron transfer in a multistep process free from any complexity imposed by preceding or following chemical reactions which occur on the timescale of conventional voltammetry.

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