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Behavior of Monoclonal Antibodies: Relation Between the Second Virial Coefficient (B 2) at Low Concentrations and Aggregation Propensity and Viscosity at High Concentrations

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ABSTRACT

Purpose

To investigate relationship between second virial coefficient B 2 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 B 2 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

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

Conclusions

B 2 can be used, within certain limitations, as an effective indicator of viscosity and aggregation propensity of highly concentrated MAb solutions.

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ACKNOWLEDGMENTS & DISCLOSURES

The authors would like to thank Daisuke Ama, Kei Kubota, Yuki Araki, Mami Mitsui and Misako Sawakuri (Daiichi Sankyo Co., Ltd., Tokyo, Japan) for their skillful technical support.

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Authors and Affiliations

  1. Analytical & Quality Evaluation Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan

    Shuntaro Saito, Jun Hasegawa, Naoki Kobayashi & Naoyuki Kishi

  2. Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Shuntaro Saito, Susumu Uchiyama & Kiichi Fukui

Authors
  1. Shuntaro Saito
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  2. Jun Hasegawa
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  3. Naoki Kobayashi
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  4. Naoyuki Kishi
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  5. Susumu Uchiyama
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  6. Kiichi Fukui
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Corresponding author

Correspondence to Kiichi Fukui.

Electronic Supplementary Material

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Supplementary Material Fig. 1

Residual plots generated from least-squares fitting of the concentration dependence of 1/M W,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)

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Saito, S., Hasegawa, J., Kobayashi, N. et al. Behavior of Monoclonal Antibodies: Relation Between the Second Virial Coefficient (B 2) at Low Concentrations and Aggregation Propensity and Viscosity at High Concentrations. Pharm Res 29, 397–410 (2012). https://doi.org/10.1007/s11095-011-0563-x

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  • DOI: https://doi.org/10.1007/s11095-011-0563-x

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