Viscosity of high concentration protein formulations of monoclonal antibodies of the IgG1 and IgG4 subclass – Prediction of viscosity through protein–protein interaction measurements

Neergaard, Martin S.; Kalonia, Devendra S.; Parshad, Henrik; Nielsen, Anders Dybdal; Möller, E; Weert, Marco van de

doi:10.1016/j.ejps.2013.04.019

Cited by 115 publications

(101 citation statements)

References 41 publications

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“…7 B. Orientation-dependent patchy interactions in proteins are captured crudely, at best, in the BSS model. We emphasize that these data invalidate the assumption that the interaction potential of mean force of protein solutions is universally independent of concentration (128,129).…”

Section: Resultsmentioning

confidence: 92%

Critical Examination of the Colloidal Particle Model of Globular Proteins

Sarangapani¹,

Hudson

Jones

et al. 2015

Biophysical Journal

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Recent studies of globular protein solutions have uniformly adopted a colloidal view of proteins as particles, a perspective that neglects the polymeric primary structure of these biological macromolecules, their intrinsic flexibility, and their ability to sample a large configurational space. While the colloidal perspective often serves as a useful idealization in many cases, the macromolecular identity of proteins must reveal itself under thermodynamic conditions in which the native state is no longer stable, such as denaturing solvents and high protein concentrations where macromolecules tend to have screened excluded volume, charge, and hydrodynamic interactions. Under extreme pH conditions, charge repulsion interactions within the protein chain can overcome the attractive hydrogen-bonding interactions, holding it in its native globular state. Conformational changes can therefore be expected to have great significance on the shear viscosity and other rheological properties of protein solutions. These changes are not envisioned in conventional colloidal protein models and we have initiated an investigation of the scattering and rheological properties of model proteins. We initiate this effort by considering bovine serum albumin because it is a globular protein whose solution properties have also been extensively investigated as a function of pH, temperature, ionic strength, and concentration. As we anticipated, near-ultraviolet circular dichroism measurements and intrinsic viscosity measurements clearly indicate that the bovine serum albumin tertiary structure changes as protein concentration and pH are varied. Our findings point to limited validity of the colloidal protein model and to the need for further consideration and quantification of the effects of conformational changes on protein solution viscosity, protein association, and the phase behavior. Small-angle Neutron Scattering measurements have allowed us to assess how these conformational changes influence protein size, shape, and interprotein interaction strength.

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Section: Resultsmentioning

confidence: 92%

Critical Examination of the Colloidal Particle Model of Globular Proteins

Sarangapani¹,

Hudson

Jones

et al. 2015

Biophysical Journal

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“…A strong correlation has been reported between decreasing values of k D or increasing values of r h,apparent measured using DLS at low antibody concentration and increased viscosity at high concentration [27]. …”

Section: Applicationsmentioning

confidence: 99%

Recent applications of light scattering measurement in the biological and biopharmaceutical sciences

Minton

2016

Analytical Biochemistry

115

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“…Thus, for antibody biopharmaceuticals, where doses of up to several mg/kg body weight is often desirable, highly concentrated solutions (up to several hundreds of mg/mL) may be required to deliver the necessary dose. At high concentrations, protein solutions (in the range of ≥100 mg/mL) can exhibit unwanted properties, such as increased levels of aggregation and viscosity levels that exceed the mechanical limits of syringes and autoinjector devices to deliver the dose [3][4][5][6]. As aggregation and high viscosity can affect biopharmaceutical manufacturing, efficacy, and administration route, it is critical to understand how and why these phenomena occur, in order to minimize or eliminate them [3,7,8].…”

Section: Introductionmentioning

confidence: 99%

Conformational Analysis of Proteins in Highly Concentrated Solutions by Dialysis-Coupled Hydrogen/Deuterium Exchange Mass Spectrometry

Houde

Nazari

Bou-Assaf

et al. 2016

J. Am. Soc. Mass Spectrom.

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Abstract. When highly concentrated, an antibody solution can exhibit unusual behaviors, which can lead to unwanted properties, such as increased levels of protein aggregation and unusually high viscosity. Molecular modeling, along with many indirect biophysical measurements, has suggested that the cause for these phenomena can be due to short range electrostatic and/or hydrophobic protein-protein interactions. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) is a useful tool for investigating protein conformation, dynamics, and interactions. However, Btraditional^continuous dilution labeling HDX-MS experiments have limited utility for the direct analysis of solutions with high concentrations of protein. Here, we present a dialysis-based HDX-MS (di-HDX-MS) method as an alternative HDX-MS labeling format, which takes advantage of passive dialysis rather than the classic dilution workflow. We applied this approach to a highly concentrated antibody solution without dilution or significant sample manipulation, prior to analysis. Such a method could pave the way for a deeper understanding of the unusual behavior of proteins at high concentrations, which is highly relevant for development of biopharmaceuticals in industry.

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Viscosity of high concentration protein formulations of monoclonal antibodies of the IgG1 and IgG4 subclass – Prediction of viscosity through protein–protein interaction measurements

Cited by 115 publications

References 41 publications

Critical Examination of the Colloidal Particle Model of Globular Proteins

Critical Examination of the Colloidal Particle Model of Globular Proteins

Recent applications of light scattering measurement in the biological and biopharmaceutical sciences

Conformational Analysis of Proteins in Highly Concentrated Solutions by Dialysis-Coupled Hydrogen/Deuterium Exchange Mass Spectrometry

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