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Effects of Charge on Antibody Tissue Distribution and Pharmacokinetics

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Department of Pharmacokinetic and Pharmacodynamic Sciences, Department of Antibody Engineering, and Department of Bioinformatics, Genentech Research and Early Development, South San Francisco, California 94080, United States
* Address correspondence to Leslie A. Khawli, Early Development Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, CA 94080. Tel. 650-225-6509; Fax 650-742-5234; E-mail: [email protected]
†Department of Pharmacokinetic and Pharmacodynamic Sciences.
‡Department of Antibody Engineering.
§Department of Bioinformatics.
Cite this: Bioconjugate Chem. 2010, 21, 12, 2153–2163
Publication Date (Web):November 5, 2010
https://doi.org/10.1021/bc100261d
Copyright © 2010 American Chemical Society

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    Abstract

    Antibody pharmacokinetics and pharmacodynamics are often governed by biological processes such as binding to antigens and other cognate receptors. Emphasis must also be placed, however, on fundamental physicochemical properties that define antibodies as complex macromolecules, including shape, size, hydrophobicity, and charge. Electrostatic interactions between anionic cell membranes and the predominantly positive surface charge of most antibodies can influence blood concentration and tissue disposition kinetics in a manner that is independent of antigen recognition. In this context, the deliberate modification of antibodies by chemical means has been exploited as a valuable preclinical research tool to investigate the relationship between net molecular charge and biological disposition. Findings from these exploratory investigations may be summarized as follows: (I) shifts in isoelectric point of approximately one pI unit or more can produce measurable changes in tissue distribution and kinetics, (II) increases in net positive charge generally result in increased tissue retention and increased blood clearance, and (III) decreases in net positive charge generally result in decreased tissue retention and increased whole body clearance. Understanding electrostatic interactions between antibodies and biological matrices holds relevance in biotechnology, especially with regard to the development of immunoconjugates. The guiding principles and knowledge gained from preclinical evaluation of chemically modified antibodies will be discussed and placed in the context of therapeutic antibodies that are currently marketed or under development, with a particular emphasis on pharmacokinetic and disposition properties.

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