Pharmaceutical Research

, Volume 29, Issue 2, pp 397–410

Behavior of Monoclonal Antibodies: Relation Between the Second Virial Coefficient (B2) at Low Concentrations and Aggregation Propensity and Viscosity at High Concentrations

  • Shuntaro Saito
  • Jun Hasegawa
  • Naoki Kobayashi
  • Naoyuki Kishi
  • Susumu Uchiyama
  • Kiichi Fukui
Research Paper

DOI: 10.1007/s11095-011-0563-x

Cite this article as:
Saito, S., Hasegawa, J., Kobayashi, N. et al. Pharm Res (2012) 29: 397. doi:10.1007/s11095-011-0563-x

ABSTRACT

Purpose

To investigate relationship between second virial coefficient B2 and viscosity and aggregation propensity of highly concentrated monoclonal antibody (MAbs) solutions.

Methods

Intermolecular interactions of 3 MAbs solutions with varying pH were characterized according to B2 estimated by analytical ultracentrifugation sedimentation equilibrium with initial loading concentrations <10 mg/mL. Viscosity measurements and stability assessments of MAb solutions at concentrations higher than 100 mg/mL were conducted.

Results

B2 of all MAb solutions depended on solution pH and have qualitative correlation with viscosity and aggregation propensity. The more negative the B2 values, the more viscous the solution, acquiring increased propensity to aggregate. Solutions with B2 values of ~2 × 10−5 mL·mol/g2 acquire similar viscosity and aggregation propensity regardless of amino acid sequences; for solutions with negative B2 values, viscosity and aggregation propensity differed depending on sequences. Results suggest attractive intermolecular interactions represented by negative B2 values are influenced by surface properties of individual MAbs.

Conclusions

B2 can be used, within certain limitations, as an effective indicator of viscosity and aggregation propensity of highly concentrated MAb solutions.

KEY WORDS

aggregation analytical ultracentrifugation sedimentation equilibrium monoclonal antibody second virial coefficient viscosity 

Supplementary material

11095_2011_563_Fig10_ESM.jpg (34 kb)
Supplementary Material Fig. 1

Residual plots generated from least-squares fitting of the concentration dependence of 1/MW,app for MAb-A (A), MAb-B(B), and MAb-C (C) in 10 mM citrate buffer containing 140 mM NaCl (pH 6). The data obtained for the entire concentration range 1 to 12 mg/mL were used for MAb-A and MAb-C. Data obtained at lower concentrations 1 to 3 mg/mL (□) and higher concentrations 4 to 12 mg/m (■) were used for MAb-B. (JPEG 33 kb)

11095_2011_563_MOESM1_ESM.tif (3.5 mb)
High Resolution Image (TIFF 3577 kb)

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Shuntaro Saito
    • 1
    • 2
  • Jun Hasegawa
    • 1
  • Naoki Kobayashi
    • 1
  • Naoyuki Kishi
    • 1
  • Susumu Uchiyama
    • 2
  • Kiichi Fukui
    • 2
  1. 1.Analytical & Quality Evaluation Research LaboratoriesDaiichi Sankyo Co., Ltd.Edogawa-kuJapan
  2. 2.Department of Biotechnology, Graduate School of EngineeringOsaka UniversitySuitaJapan

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