Rheological and syringeability properties of highly concentrated human polyclonal immunoglobulin solutions

Burckbuchler, Virginie; Mekhloufi, Ghozlène; Giteau, Alexandra; Grossiord, J. L.; Huille, Sylvain; Agnely, Florence

doi:10.1016/j.ejpb.2010.08.002

Cited by 134 publications

(91 citation statements)

References 31 publications

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“…8 The self-associated species can pose manufacturing and delivery challenges (e.g., high viscosity, clogging of the lines and filters 3,9 ) or cause pain to patients upon administration. 10,11 In certain cases, the self-associated species can affect bioactivity and pharmacokinetic properties of biologic drug candidates 12,13 or, depending on the structural and environmental conditions, transform to irreversible aggregates via further covalent linkages. 14 A number of studies have illustrated the diversity of structural mechanisms by which self-association can occur.…”

Section: Introductionmentioning

confidence: 99%

Mitigation of reversible self-association and viscosity in a human IgG1 monoclonal antibody by rational, structure-guided Fv engineering

Geoghegan¹,

Fleming²,

Damschroder³

et al. 2016

mAbs

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Undesired solution behaviors such as reversible self-association (RSA), high viscosity, and liquid-liquid phase separation can introduce substantial challenges during development of monoclonal antibody formulations. Although a global mechanistic understanding of RSA (i.e., native and reversible proteinprotein interactions) is sufficient to develop robust formulation controls, its mitigation via protein engineering requires knowledge of the sites of protein-protein interactions. In the study reported here, we coupled our previous hydrogen-deuterium exchange mass spectrometry findings with structural modeling and in vitro screening to identify the residues responsible for RSA of a model IgG1 monoclonal antibody (mAb-C), and rationally engineered variants with improved solution properties (i.e., reduced RSA and viscosity). Our data show that mutation of either solvent-exposed aromatic residues within the heavy and light chain variable regions or buried residues within the heavy chain/light chain interface can significantly mitigate RSA and viscosity by reducing the IgG's surface hydrophobicity. The engineering strategy described here highlights the utility of integrating complementary experimental and in silico methods to identify mutations that can improve developability, in particular, high concentration solution properties, of candidate therapeutic antibodies.

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Section: Introductionmentioning

confidence: 99%

Mitigation of reversible self-association and viscosity in a human IgG1 monoclonal antibody by rational, structure-guided Fv engineering

Geoghegan¹,

Fleming²,

Damschroder³

et al. 2016

mAbs

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show abstract

“…The syringeability of the gels is given in Table 2. It is shown that the force required for all values described was \30 N, which is suggested as the limit of manual injection force [46]. Also, it was observed that the addition of CaP compounds did not have a significant effect on the syringeability of the gel samples.…”

Section: Syringeabilitymentioning

confidence: 96%

Injectable gel from squid pen chitosan for bone tissue engineering applications

Shavandi

Bekhit

Sun

et al. 2015

J Sol-Gel Sci Technol

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The aim of this study was to evaluate the potential of squid pen chitosan for developing injectable gels for bone tissue engineering applications. Gel mixtures made of glycerol phosphate mixed with crab (RC) or squid pen (RS) chitosan (2 % w/v) at four different concentrations (0, 30, 50 and 70 %) of calcium phosphate compounds (CaP, hydroxyapatite and b-tricalcium phosphate, HA/b-TCP) were investigated for their biocompatibility and mechanical properties. The proposed gel rapidly settled (\3 min) and formed a stable gel at body temperature (i.e. 37°C). The chemical compositions and crystallinity of the gels were characterised by FTIR and XRD. The surface morphology and microstructure of the gels were characterised using SEM. The physical properties (such as water uptake, washout resistant and syringeability), compressive modulus and biocompatibility properties (cell cytotoxicity) of the gels were also studied. The RS chitosan gels showed the highest water uptake ability ([2000 %), compressive modulus (up to 26 kPa) and better cell (Saos-2) compatibility compared to the RC chitosan. This study showed that RS chitosan is a promising alternative to commercially available crab/shrimp chitosan for producing injectable gels for tissue engineering applications. Graphical AbstractKeywords Squid pen chitosan Á Glycerol phosphate Á Injectable Á Calcium phosphate Á Gel

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“…The temperature is measured from thermistor inside the aluminum block and is not in sample materials. (1) shows an example cooling step and inset (2) shows an example heating step. Note that incremental steps in the heating mode to prevent temperature overshoot.…”

Section: Temperature Controlmentioning

confidence: 99%

“…11,12,36 The rheological properties of a sample are calculated from the dynamics of the embedded probe particles. The ensembleaveraged mean square displacement (MSD), hDx 2 ðsÞi, is calculated from the probe trajectories at each lag time s. The Generalized Stokes-Einstein Relation (GSER) 11 relates the MSD to bulk rheological properties by JðsÞ ¼ 3pahDx 2 i=kT, where J(s) is the material creep compliance, s is the lag time, a is the probe radius, and kT is the thermal energy. In the limit for a material with Newtonian viscosity g, JðsÞ ¼ s=g, and the GSER simplifies to the familiar Stokes-EinsteinSutherland equation…”

Section: Multiple Particle Tracking (Mpt) Experimentsmentioning

confidence: 99%

“…1 Protein solution rheology is one of the critical physical properties that is measured during early stage development, as viscosity affects syringeability 2 and manufacturability, 3 and may indicate self-associating protein-protein interactions, 4 thermal stability, 5 or protein aggregation propensity. 6 The effects of temperature on solution viscosity require thorough examination, as drug product manufacturing units operate at different temperatures: tangential flow filtrations and thermal stability studies are often conducted at elevated temperatures (>30 C), 7,8 whereas protein solutions are refrigerated during storage and transportation.…”

Section: Introductionmentioning

confidence: 99%

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Parallel temperature-dependent microrheological measurements in a microfluidic chip

Josephson

Galush²,

Furst

2016

Biomicrofluidics

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Microfluidic stickers are used as a sample environment to measure the microrheology of monoclonal antibody (mAb) protein solutions. A Peltier-based microscope stage is implemented and validated, and is capable of controlling the sample temperature over the range 0.9-40 C. The design accounts for heat transfer to and from the objective, controls the sample environment humidity to mitigate condensation, and provides adequate damping to reduce vibration from the cooling system. A concentrated sucrose solution is used as a standard sample to provide an in situ temperature measurement by the Stokes-Einstein-Sutherland relation. By combining microfluidic stickers and microrheology, 72 temperature-concentration viscosity measurements of mAb solutions can be made in 1 day, a significant increase in throughput over conventional rheometry. Published by AIP Publishing. [http://dx

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Rheological and syringeability properties of highly concentrated human polyclonal immunoglobulin solutions

Cited by 134 publications

References 31 publications

Mitigation of reversible self-association and viscosity in a human IgG1 monoclonal antibody by rational, structure-guided Fv engineering

Mitigation of reversible self-association and viscosity in a human IgG1 monoclonal antibody by rational, structure-guided Fv engineering

Injectable gel from squid pen chitosan for bone tissue engineering applications

Parallel temperature-dependent microrheological measurements in a microfluidic chip

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