Polar Solvents Decrease the Viscosity of High Concentration IgG1 Solutions Through Hydrophobic Solvation and Interaction: Formulation and Biocompatibility Considerations

Kamerzell, Tim J.; Pace, Amanda L.; Li, Megan; Danilenko, Dimitry M.; Mcdowell, Michelle; Gokarn, Yatin R.; Wang, Y. John

doi:10.1002/jps.23453

Cited by 20 publications

(8 citation statements)

References 38 publications

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“…The sample viscosity at which the effect started to occur in our tested system was approximately 9 cP ( Fig. 2a), a value that can easily be reached in concentrated protein formulations (8).…”

Section: Resultsmentioning

confidence: 74%

Light Obscuration Measurements of Highly Viscous Solutions: Sample Pressurization Overcomes Underestimation of Subvisible Particle Counts

Weinbuch

Jiskoot

Hawe³

2014

AAPS J

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Light obscuration (LO) is the current standard technique for subvisible particle analysis in the quality control of parenterally administered drugs, including therapeutic proteins. Some of those, however, exhibit high viscosities due to high protein concentrations, which can lead to false results by LO measurements. In this study, we show that elevated sample viscosities, from about 9 cP, lead to an underestimation of subvisible particle concentrations, which is easily overlooked when considering reported data alone. We evaluated a solution to this problem, which is the application of sample pressurization during analysis. The results show that this is an elegant way to restore the reliability of LO analysis of highly viscous products without the necessity of additional sample preparation.

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Section: Resultsmentioning

confidence: 74%

Light Obscuration Measurements of Highly Viscous Solutions: Sample Pressurization Overcomes Underestimation of Subvisible Particle Counts

Weinbuch

Jiskoot

Hawe³

2014

AAPS J

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“…10 Hydrophobic salts and excipients, polar solvents, non-aqueous organic suspensions and gel beads can help reduce solution viscosity. 1,[37][38][39] In practice, overcoming the challenges posed by high viscosity for an antibody candidate already in development by altering solution buffer characteristics is a timeconsuming, resource-intensive, trial and error process that is preferably avoided.…”

Section: Discussionmentioning

confidence: 99%

Rational design of viscosity reducing mutants of a monoclonal antibody: Hydrophobic versus electrostatic inter-molecular interactions

Nichols

Kumar

et al. 2015

mAbs

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High viscosity of monoclonal antibody formulations at concentrations ≥100 mg/mL can impede their development as products suitable for subcutaneous delivery. The effects of hydrophobic and electrostatic intermolecular interactions on the solution behavior of MAB 1, which becomes unacceptably viscous at high concentrations, was studied by testing 5 single point mutants. The mutations were designed to reduce viscosity by disrupting either an aggregation prone region (APR), which also participates in 2 hydrophobic surface patches, or a negatively charged surface patch in the variable region. The disruption of an APR that lies at the interface of light and heavy chain variable domains, VH and VL, via L45K mutation destabilized MAB 1 and abolished antigen binding. However, mutation at the preceding residue (V44K), which also lies in the same APR, increased apparent solubility and reduced viscosity of MAB 1 without sacrificing antigen binding or thermal stability. Neutralizing the negatively charged surface patch (E59Y) also increased apparent solubility and reduced viscosity of MAB 1, but charge reversal at the same position (E59K/R) caused destabilization, decreased solubility and led to difficulties in sample manipulation that precluded their viscosity measurements at high concentrations. Both V44K and E59Y mutations showed similar increase in apparent solubility. However, the viscosity profile of E59Y was considerably better than that of the V44K, providing evidence that inter-molecular interactions in MAB 1 are electrostatically driven. In conclusion, neutralizing negatively charged surface patches may be more beneficial toward reducing viscosity of highly concentrated antibody solutions than charge reversal or aggregation prone motif disruption.

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“…The authors tested 43 different salts and achieved up to 10-fold reduction in viscosity using salts of camphor sulfonic acid. Kamerzell et al 83 have also studied polar salts, dimethyl sulfoxide and dimethylacetamide. The authors found that these salts decrease the viscosity of the antibody solutions by preferentially solvating hydrophobic residues and disrupting intermolecular interactions.…”

Section: Strategy Iii: Optimizing Formulation For Reduced Viscositymentioning

confidence: 99%

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Tomar

Kumar

Singh

et al. 2016

mAbs

162

145

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Effective translation of breakthrough discoveries into innovative products in the clinic requires proactive mitigation or elimination of several drug development challenges. These challenges can vary depending upon the type of drug molecule. In the case of therapeutic antibody candidates, a commonly encountered challenge is high viscosity of the concentrated antibody solutions. Concentration-dependent viscosity behaviors of mAbs and other biologic entities may depend on pairwise and higher-order intermolecular interactions, non-native aggregation, and concentration-dependent fluctuations of various antibody regions. This article reviews our current understanding of molecular origins of viscosity behaviors of antibody solutions. We discuss general strategies and guidelines to select low viscosity candidates or optimize lead candidates for lower viscosity at early drug discovery stages. Moreover, strategies for formulation optimization and excipient design are also presented for candidates already in advanced product development stages. Potential future directions for research in this field are also explored.

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Polar Solvents Decrease the Viscosity of High Concentration IgG1 Solutions Through Hydrophobic Solvation and Interaction: Formulation and Biocompatibility Considerations

Cited by 20 publications

References 38 publications

Light Obscuration Measurements of Highly Viscous Solutions: Sample Pressurization Overcomes Underestimation of Subvisible Particle Counts

Light Obscuration Measurements of Highly Viscous Solutions: Sample Pressurization Overcomes Underestimation of Subvisible Particle Counts

Rational design of viscosity reducing mutants of a monoclonal antibody: Hydrophobic versus electrostatic inter-molecular interactions

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

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