Effects of Charge on Antibody Tissue Distribution and Pharmacokinetics
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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Factors influencing mAbs distribution to individual organs or tissues include drug-specific features such as binding affinity to target antigens, target internalization rate, mAb hydrophilicity, and charge, and tissue-specific features such as membrane structure and blood flow.
“Additional factors influencing mAbs distribution to individual organs or tissues include: drug‐specific features such as their binding affinity to specific target antigens, targets internalization rate,24 mAb hydrophilicity, charge,25 and tissue‐specific features such as membrane structure and blood flow.26”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [25]
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Zheng, Y., Tesar, D. B., Benincosa, L., Birnböck, H., Boswell, C. A., Bumbaca, D., Cowan, K. J., Danilenko, D. M., Daugherty, A. L., Fielder, P. J., et al. (2012) · mAbs · doi:10.4161/mabs.4.2.19387 · Cited by 149 · see citing works
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Physiochemical and Biochemical Factors Influencing the Pharmacokinetics of Antibody Therapeutics
Bumbaca, D., Boswell, C. A., Fielder, P. J., & Khawli, L. A. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9369-y · Cited by 119 · see citing works
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Bumbaca Yadav, D., Sharma, V. K., Boswell, C. A., Hotzel, I., Tesar, D., Shang, Y., Ying, Y., Fischer, S. K., Grogan, J. L., Chiang, E. Y., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.692434 · Cited by 82 · see citing works
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Assessments of antibody biodistribution
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- Authors
- Boswell, C. A., Tesar, D. B., Mukhyala, K., Theil, F.-P., Fielder, P. J., & Khawli, L. A.
- Affiliations
- Genentech (US)
- Corresponding author
- Khawli, Leslie A.
- Venue
- Bioconjugate Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-11-05
- Volume
- 21
- Issue
- 12
- Pages
- 2153-2163
- ISSN
- 1043-1802 (ISSN-L)
- 1520-4812
- OpenAlex
- W2078317394
- Cited by
- 398
- References
- 104
- Citations by year
- 2026: 22 · 2025: 15 · 2024: 38 · 2023: 32 · 2022: 31 · 2021: 41 · 2020: 21 · 2019: 35 · 2018: 30 · 2017: 25 · 2016: 15 · 2015: 26 · 2014: 20 · 2013: 20 · 2012: 19
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioconjugate Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genentech
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- net positive charge, isoelectric point, tissue distribution, pharmacokinetics, electrostatic interactions, tissue retention, blood clearance, immunoconjugates, therapeutic antibodies
- MeSH terms
- Animals, Anions, Antibodies, Antigens, Cations, Cell Membrane, Drug Evaluation, Preclinical, Female, Humans, Isoelectric Point, Models, Molecular, Neoplasms, Protein Binding, Tissue Distribution, Protein Engineering, Immunoconjugates, Mice, Rats, Static Electricity, Hydrophobic and Hydrophilic Interactions, Molecular Targeted Therapy
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