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Comparison of Succinimidyl [125I]Iodobenzoate with Iodogen Iodination Methods to Study Pharmacokinetics and ADME of Biotherapeutics

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ABSTRACT

Purpose

To assess the application of succinimidyl iodobenzoate (SIB) iodination method in labeling biotherapeutics to study their pharmacokinetics (PK) and biodistribution.

Method

An IgG molecule (protein-01) and a 40 KDa protein (protein-02) were evaluated. Pharmacokinetics (PK) and biodistribution of the radiolabeled IgG (125I-protein-01) in mice compared parameters from SIB and Iodogen protein iodination labeling methods. In addition, PK of radiolabeled 40 KDa protein (125I-protein-02) using SIB was compared with non-labeled protein-02 analyzed by ligand binding assay (LBA).

Results

Up to 72 h following a single IP injection to mice, the percentage of “free-label” determined by the soluble counts after TCA precipitation to total radioactivity in serum samples was 2.8–49.4% vs. <1.0% for 125I-protein-01 iodinated via Iodogen or SIB methods, respectively, suggesting a higher in vivo stability of 125I-protein-01 labeled via the SIB method. The serum exposure of 125I-protein-01 was two-fold higher, and correspondingly, the tissue exposure was also higher (averaging 3.6 fold at 168 h) when using SIB protein labeling method than when using the Iodogen method. In addition, following subcutaneous (SC) administration to mice, the serum exposure of 125I-protein-02 labeled via SIB method was similar to protein-02 measure by LBA.

Conclusion

In this study, iodination of proteins using SIB methodology has overcome the dehalogenation problem in vivo which is inherent in Iodogen method, and PK parameters of a protein iodinated via SIB were comparable to the un-labeled protein measured by LBA. The SIB iodination method is an improved labeling approach for biotherapeutics used in studying PK and biodistribution characteristics.

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Abbreviations

Ab:

Antibody

ADME:

Absorption, distribution, metabolism, excretion

AUC:

Area under concentration versus time curve

IP:

Intraperitoneal

LBA:

Ligand-binding assays

LC-MS:

Liquid chromatography-mass spectrometry

mAb:

Monoclonal antibody

MW:

Molecular weight

NCS:

N-chlorosuccinimide

PBS:

Phosphate buffered saline

PK:

Pharmacokinetics

RCP:

Radiochemical purity

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SEC:

Size exclusion chromatogram

SIB:

Succinimidyl iodobenzoate

TCA:

Trichloroacetic acid

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ACKNOWLEDGEMENTS AND DISCLOSURES

The authors would like to thank members of the Department of Comparative Medicine, Pfizer Inc, Andover, for conducting in-life animal studies; and to thank Yan Weng and Martin Dowty for providing the proteins.

Author information

Author notes

  1. Xin Xu

    Present address: National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Dr., Rockville, Maryland, 20850, USA

Authors and Affiliations

  1. Department of Clinical & Translational Imaging, Precision Medicine, Pfizer Inc, Cambridge, Massachusetts, 02139, USA

    Jianqing Chen

  2. Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, One Burtt Road, Andover, Massachusetts, 01810, USA

    Mengmeng Wang, Alison Joyce, Mania Kavosi & Denise M. O’Hara

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  1. Jianqing Chen
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  2. Mengmeng Wang
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Correspondence to Mengmeng Wang.

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Chen, J., Wang, M., Joyce, A. et al. Comparison of Succinimidyl [125I]Iodobenzoate with Iodogen Iodination Methods to Study Pharmacokinetics and ADME of Biotherapeutics. Pharm Res 31, 2810–2821 (2014). https://doi.org/10.1007/s11095-014-1378-3

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  • DOI: https://doi.org/10.1007/s11095-014-1378-3

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