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Pharmaceutical Research

, Volume 34, Issue 1, pp 193–207 | Cite as

Contrasting the Influence of Cationic Amino Acids on the Viscosity and Stability of a Highly Concentrated Monoclonal Antibody

  • Barton J. Dear
  • Jessica J. Hung
  • Thomas M. Truskett
  • Keith P. Johnston
Research Paper

Abstract

Purpose

To explain the effects of cationic amino acids and other co-solutes on the viscosity, stability and protein-protein interactions (PPI) of highly concentrated (≥200 mg/ml) monoclonal antibody (mAb) solutions to advance subcutaneous injection.

Methods

The viscosities of ≥200 mg/ml mAb1 solutions with various co-solutes and pH were measured by capillary rheometry in some cases up to 70,000 s−1. The viscosities are analyzed in terms of dilute PPI characterized by diffusion interaction parameters (k D ) from dynamic light scattering (DLS). MAb stability was measured by turbidity and size exclusion chromatography (SEC) after 4 weeks of 40°C storage.

Results

Viscosity reductions were achieved by reducing the pH, or adding histidine, arginine, imidazole or camphorsulfonic acid, each of which contains a hydrophobic moiety. The addition of inorganic electrolytes or neutral osmolytes only weakly affected viscosity. Systems with reduced viscosities also tended to be Newtonian, while more viscous systems were shear thinning.

Conclusions

Viscosity reduction down to 20 cP at 220 mg/ml mAb1 was achieved with co-solutes that are both charged and contain a hydrophobic interaction domain for sufficient binding to the protein surface. These reductions are related to the DLS diffusion interaction parameter, k D , only after normalization to remove the effect of charge screening. Shear rate profiles demonstrate that select co-solutes reduce protein network formation.

KEY WORDS

antibody arginine histidine rheology viscosity 

Abbreviations

CF

Centrifugal filtration

CSA

Camphorsulfonic acid

DLS

Dynamic light scattering

Gdm

Guanidinium

Im

Imidazole

kD

Diffusion interaction parameter

LD

Lyophilization dilution

mAb

Monoclonal antibody

pI

Isoelectric point

PPI

Protein-protein interactions

Tre

Trehalose

ηinh

Inherent viscosity

Notes

Acknowledgments and Disclosures

We acknowledge support from AbbVie, the National Science Foundation (12474795) and the Welch Foundation (KPJ F-1319 and TMT F-1696). We thank Christian Reid for useful comments during the course of this work.

Supplementary material

11095_2016_2055_MOESM1_ESM.docx (1.7 mb)
ESM 1 (DOCX 1787 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Barton J. Dear
    • 1
  • Jessica J. Hung
    • 1
  • Thomas M. Truskett
    • 1
  • Keith P. Johnston
    • 1
  1. 1.McKetta Department of Chemical EngineeringThe University of Texas at AustinAustinUSA

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