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.

Target-independent variable region mediated effects on antibody clearance can be FcRn independent

“…Looking at the cause of nonspecificity in briakinumab, the charge dependence of this phenotype was consistent with our BLI experiments, and is consistent with previous findings that positively charged patches can lead to increased nonspecific binding to cells and other proteins. 12,18,[38][39][40] These results are also consistent with a similar study using the IgG4 isotype, in which a higher pI led to a shortened half-life and higher clearance rates regardless of presence of FcRn. 15 Studies on larger sets of antibodies suggest that the correlation between pI and clearance rates is not generalizable; 24,25 however, a localized patch of positive charge may be sufficient to increase interactions with the negatively charged surface of cell membranes.…”

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

“…Labels may also alter the protein biodistribution through non-specific changes (18) in bulk, charge, or hydrophobic interactions. This has been a major barrier to the adoption of many otherwise excellent fluorescent labels.…”

Tailoring recombinant protein quality by rational media design

“…The efficacy, potency and safety depend on the structural characteristics of the protein entity 11 , which explains the particular attention paid in biotherapeutic development to post-translational modifications that the expressed protein may undergo 1,12,14,[39][40][41] . In the particular case of monoclonal antibodies (mAbs), increased antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the major objectives to increase the immune response of the human body and thus clinical efficacy 42 .…”

“…In the particular case of monoclonal antibodies (mAbs), increased antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the major objectives to increase the immune response of the human body and thus clinical efficacy 42 . Many studies have addressed various effects of glycosylation and charge variants on the biological activity and pharmacokinetics 11,40,43,44 . On that account, it is of utmost importance to understand the glycosylation process and how it is influenced by cell culture variations in bioprocess development and manufacturing in order to manage to control and optimize the glycan pattern 24 .…”

“…On that account, it is of utmost importance to understand the glycosylation process and how it is influenced by cell culture variations in bioprocess development and manufacturing in order to manage to control and optimize the glycan pattern 24 . As a result, efforts to develop techniques to alter the properties of therapeutic proteins have multiplied, aiming to improve clinical utility with respect to antigen targeting and potency 40 .…”