Structure-Activity Relationship for Hydrophobic Salts as Viscosity-Lowering Excipients for Concentrated Solutions of Monoclonal Antibodies

Guo, Zhenming; Chen, Alvin; Nassar, Roger A.; Helk, Bernhard; Mueller, Claudia; Tang, Yu; Gupta, Kapil; Klibanov, Alexander M.

doi:10.1007/s11095-012-0802-9

Cited by 53 publications

(51 citation statements)

References 19 publications

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“…Two recent studies have shown that hydrophobic organic salts can significantly diminish the viscosity of high-concentration antibody solutions, suggesting these bulky organic salt molecules can disrupt the intermolecular transient networks between protein molecules because of their apolarity. 18,19 The results of He et al 20 concerning the effect of sugars on the viscosity of antibody solutions also support a related conclusion because these sugars, lacking both significant apolarity and charge, were found to further increase the viscosity of antibody solutions. 20 In a more recent study, the viscosity of antibody mixtures was found to be reasonably described as the geometric sum of the viscosity of each solution, 21 suggesting that related protein-protein interactions are nonspecific in nature.…”

Section: Introductionmentioning

confidence: 63%

“…In addition, the significance and contribution of each of the possible noncovalent interactions, in combination with charge–charge interactions, to the overall viscosity of a high‐concentration protein solution remain unclear. Two recent studies have shown that hydrophobic organic salts can significantly diminish the viscosity of high‐concentration antibody solutions, suggesting these bulky organic salt molecules can disrupt the intermolecular transient networks between protein molecules because of their apolarity . The results of He et al concerning the effect of sugars on the viscosity of antibody solutions also support a related conclusion because these sugars, lacking both significant apolarity and charge, were found to further increase the viscosity of antibody solutions .…”

Section: Introductionmentioning

confidence: 82%

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Linking the Solution Viscosity of an IgG2 Monoclonal Antibody to Its Structure as a Function of pH and Temperature

Cheng

Joshi

Jain

et al. 2013

Journal of Pharmaceutical Sciences

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Section: Introductionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 82%

Linking the Solution Viscosity of an IgG2 Monoclonal Antibody to Its Structure as a Function of pH and Temperature

Cheng

Joshi

Jain

et al. 2013

Journal of Pharmaceutical Sciences

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“…Klibanov and coworkers 82 have studied the effect of hydrophobic salts on the viscosity of antibody solutions at 100 mg per mL concentration. The authors tested 43 different salts and achieved up to 10-fold reduction in viscosity using salts of camphor sulfonic acid.…”

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

152

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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“…42,46 Another Camphor-10-sulfonic acid salt reduced viscosity 10-fold. 46 Hydrophobic attraction forces responsible for increased viscosity may be disrupted by these hydrophobic excipients, thereby reducing viscosity. 47 At high concentrations and corresponding close intermolecular distances, protein-protein interactions may be driven by local surface charge patches rather than the net charge on the protein.…”

Section: Viscosity Dependenciesmentioning

confidence: 99%

High concentration biotherapeutic formulation and ultrafiltration: Part 1 pressure limits

Lutz¹,

Arias²,

Zhang³

2016

Biotechnology Progress

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High therapeutic dosage requirements and the desire for ease of administration drive the trend to subcutaneous administration using delivery systems such as subcutaneous pumps and prefilled syringes. Because of dosage volume limits, prefilled syringe administration requires higher concentration liquid formulations, limited to about 30 cP or roughly 100-300 g L for mAb's. Ultrafiltration (UF) processes are routinely used to formulate biological therapeutics. This article considers pressure constraints on the UF process that may limit its ability to achieve high final product concentrations. A system hardware analysis shows that the ultrafiltration cassette pressure drop is the major factor limiting UF systems. Additional system design recommendations are also provided. The design and performance of a new cassette with a lower feed channel flow resistance is described along with 3D modeling of feed channel pressure drop. The implications of variations in cassette flow channel resistance for scaling up and setting specifications are considered. A recommendation for a maximum pressure specification is provided. A review of viscosity data and theory shows that molecular engineering, temperature, and the use of viscosity modifying excipients including pH adjustment can be used to achieve higher concentrations. The combined use of a low pressure drop cassette with excipients further increased final concentrations by 35%. Guidance is provided on system operation to control hydraulics during final concentration. These recommendations should allow one to design and operate systems to routinely achieve the 30 cP target final viscosity capable of delivery using a pre-filled syringe. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:113-124, 2017.

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Structure-Activity Relationship for Hydrophobic Salts as Viscosity-Lowering Excipients for Concentrated Solutions of Monoclonal Antibodies

Abstract: To be potent viscosity-lowering excipients, the ionic constituents of the salts must be hydrophobic, bulky, and aliphatic. A mechanistic hypothesis explaining the observed salt effects on MAb solutions' viscosities was proposed and verified.

Cited by 53 publications

References 19 publications

Linking the Solution Viscosity of an IgG2 Monoclonal Antibody to Its Structure as a Function of pH and Temperature

Linking the Solution Viscosity of an IgG2 Monoclonal Antibody to Its Structure as a Function of pH and Temperature

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

High concentration biotherapeutic formulation and ultrafiltration: Part 1 pressure limits

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