The molecular basis of high viscosity of monoclonal antibodies (mAbs) at high concentration

Shire, Steven J.

doi:10.1016/b978-0-08-100296-4.00009-9

Cited by 4 publications

(3 citation statements)

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“…It offers the possibility to work with a wide range of temperatures and concentrations from a small amount of powder [18]. The calculation of the diffusion coefficient D is related to the radius R of the particles by the Stokes-Einstein equation [19]: D = kT/6πηR, where k is the Boltzmann's constant, T the temperature, R the radius of a particle and η the viscosity of the solution (in this study, the viscosity values are: ηethanol = 1.07 × 10 −3 Pa•s and ηisopropanol = 2.37 × 10 −3 Pa•s.) Coatings 2020, 10, x FOR PEER REVIEW 3 of 16 a particle size below 1 µm, which allows a stable and reproducible suspension to be obtained without the use of dispersant.…”

Section: Measurement Of the Particle Size Distributionmentioning

confidence: 99%

Electrophoretic Deposition of 45S5 Bioglass® Coatings on the Ti6Al4V Prosthetic Alloy with Improved Mechanical Properties

et al. 2020

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In this paper, 45S5 Bioglass® coatings were elaborated by electrophoretic deposition (EPD) on the titanium alloy Ti6Al4V. An adequate grinding protocol was developed to obtain a stable suspension of submicrometric particles in isopropanol. The voltage and the deposition time of EPD were optimized. An optimal voltage of 30 V and two deposition times (30 and 90 s) were chosen to obtain two different coatings with thicknesses of 21 and 85 µm, respectively. The as-deposited coatings were thermally treated following a two-step protocol: one hour at 120 °C followed by one hour at 450 °C. The surface morphology and the chemical analysis of the 45S5 Bioglass® coatings were assessed, before and after heat treatment, by scanning electron microscopy associated to X-ray microanalysis (SEM-EDXS). Their structural analysis was performed by X-ray diffraction (XRD). A scratch test study was developed for mechanical properties analysis. The obtained results revealed that the obtained coatings were homogeneous, weakly crystallized with an important compactness. An increase in the critical load LC associated with the cohesive limit of the film (from Lc = 3.39 N to Lc = 5.18 N) was observed when the coating thickness was decreased from 85 to 21 µm. After the thermal treatment, the chemical composition of the coatings was not altered, and their mechanical properties were improved.

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Section: Measurement Of the Particle Size Distributionmentioning

confidence: 99%

Electrophoretic Deposition of 45S5 Bioglass® Coatings on the Ti6Al4V Prosthetic Alloy with Improved Mechanical Properties

et al. 2020

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“…Major traditional viscosity measurement techniques include capillary viscometers, 9,10 rotational viscometers, 11 coaxial cylinder viscometers, 12 falling ball viscometers, 13,14 and vibrational viscometers. 15 These traditional viscometers often use large sample volumes in the millilitre (mL) range to quantify the viscosity of fluids, which is highly undesirable for point of care applications. 16 There is a growing demand for robust, portable platforms to rapidly and cost efficiently measure fluid viscosity at the point of need using sample volumes in the μL to nL range.…”

Section: Introductionmentioning

confidence: 99%

Machine learning based microfluidic sensing device for viscosity measurements

Mustafa,

Haider,

Barua

et al. 2023

Sens. Diagn.

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“…218 A photodetector captures these fluctuations, mathematically processed to obtain the diffusion coefficient (D), which measures particle mobility influenced by size, temperature, and viscosity. 219 Using the Stokes-Einstein equation 220 the hydrodynamic radius (r) is calculated, representing the effective size of particles, considering both their dimensions and interaction with the surrounding fluid. 221…”

Section: Synthesis Of Diacyl Dimer Analoguementioning

confidence: 99%

Developing Novel Lipidated Glycotherapeutics

Stewart

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This thesis is comprised of two distinct sections.The first section, Chapters 2 to 4, focuses on developing novel dendritic heparan sulfate (HS) mimetics for potential use as anti-cancer and anti-viral agents. This includes the design, synthesis, and purification of sulfated mimetics and their bioisosteric analogues.HS is a naturally occurring glycosaminoglycan (GAG) widely present in mammalian tissues. Its complex structure and negative charge allow it to interact with a plethora of different proteins, playing many roles in physiological processes. Additionally, HS-protein interactions are implicated in several diseases, including viral infections, neurodegenerative disorders, and different types of cancer. These conditions have been associated with altered HS and HS binding protein levels and disrupted HS biosynthesis. Therefore, HS-protein interactions have emerged as viable therapeutic targets.Research into HS-protein interactions has led to the design of compounds that mimic the structure of HS, showing promising results for treating various diseases, such as cancer and Alzheimer's disease. However, these compounds require complex and costly syntheses. In response, the Ferrier Research Institute has designed and synthesised simpler tetramer dendritic mimetics. These novel compounds not only exhibit biological activity comparable to established HS mimetics, but their production involves fewer steps and incurs lower costs. Consequently, trimer analogues were synthesised in a previous investigation, assessing the minimal complexity required for an effective dendrimer. This study also introduced an element of lipophilicity, a characteristic found in other mimetics but absent in the tetramer, potentially enabling their integration into the cell membrane.This thesis will detail the synthesis of a sulfated dimer analogue and evaluates its antiviral efficacy relative to trimer and tetramer counterparts, aiming to establish the simplest dendrimer configuration that maintains significant biological activity. Furthermore, the work investigates the synthesis of a diacyl dimer to quantify the effect of increased lipophilicity on biological activity, informed by prior findings that suggest lipophilic attributes can enhance the biological performance of HS mimetics. Another key focus of this thesis is the investigation of the influence of bioisosteres on biological activity. While the importance of the negative charge imparted by the sulfate group in cancer and viral entry is well-established, it has yet to be determined whether this negative charge must specifically originate from a sulfate group. Therefore, bioisosteres such as phosphates and phosphorothioates, which maintain the required tetrahedral geometry while providing a negative charge, may serve as effective alternatives. The synthesis and purification of such bioisosteric analogues are also described and comparisons to their sulfated counterparts based on the available data are made.Preliminary antiviral screening has been conducted against pathogens known to utilise HS for cell entry, including Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Vaccinia Virus (VACV), and Human Papillomavirus (HPV). The findings demonstrate that sulfated analogues exhibit superior potency and lower cytotoxicity across all assays. Furthermore, an observed trend suggests that an increase in lipophilicity correlates with heightened cytotoxicity. In the case of HPV, all compounds exhibited high activity and low toxicity, though the phosphates were still marginally less effective than the sulfates.In Chapter 5, the thesis elaborates on the development of a novel native chemical ligation (NCL) method utilising a 1,2-dithiolan-4-yl carboxylate ester. The formulation of this method was driven by the need to overcome the intrinsic challenges associated with the creation of a reactive C-terminal thioester inherent in conventional NCL processes. The curated 1,2-dithiolan-4-yl carboxylate ester surfaced as a potential alternative, anticipated to maintain stability up until the selective induction of the NCL reaction, commonly facilitated by reducing agents such as tris(2-carboxyethyl)phosphine (TCEP). Notably, the refined methodology resulted in the successful execution of NCL on several peptide sequences, underscoring the versatility and applicability of the devised approach. However, complications arose when applying the methodology to the synthesis of an α-galactosylceramide (α-GalCer) based vaccine against Human Papillomavirus (HPV), a notable oncovirus. The research journey was marked by significant complexities and unforeseen challenges. Despite exhaustive efforts, the synthesis of the vaccine precursor remained unattainable, representing a significant and central challenge in this thesis.Although this thesis establishes a novel native NCL methodology, the instability of the immediate 1,2-dithiolan-4-yl carboxylate ester precursor suggests that its practical application is currently limited. Future research may focus on developing a more stable synthetic route for this precursor.

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The molecular basis of high viscosity of monoclonal antibodies (mAbs) at high concentration

Cited by 4 publications

References 60 publications

Electrophoretic Deposition of 45S5 Bioglass® Coatings on the Ti6Al4V Prosthetic Alloy with Improved Mechanical Properties

Electrophoretic Deposition of 45S5 Bioglass® Coatings on the Ti6Al4V Prosthetic Alloy with Improved Mechanical Properties

Machine learning based microfluidic sensing device for viscosity measurements

Developing Novel Lipidated Glycotherapeutics

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