Furthermore, since selecting the best candidates during early preclinical phases of product development can substantially decrease time and cost of development, it is of great importance to consider de-risk strategies and tools during drug discovery and development, including antibody variable region charge and antibody pI analyses (7-9). In any case, it is encouraged that pI values are reported in studies as an important factor influencing antibody behavior. Small changes of pI during the routine manufacturing of mAb charge variants, however, are not expected to result in dramatic changes and may not require extensive analyses (6). In summary, pI of mAbs is known to have a substantial effect on PK behavior independent of recycling mediated by the neonatal Fc receptor, FcRn.
CALCULATE PI ISOELECTRIC POINT PATCH
Even subtle manipulation such as molecular surface remodeling to disrupt positive patch regions can influence PK properties (5). It is generally observed that increases in net positive charge of antibodies result in increased blood clearance and increased tissue retention with shorter half-life, whereas antibodies with lower pI generally have decreased tissue uptake and longer half-life (1-3), although observations can be conflicting regarding correlation between mAb clearance and pI (4). Therapeutic antibodies with pI values in the range of 8-9 are taken up adequately after administration since the physiological pH is 7.4, however, in some cases antibodies have a pI outside of this range or have been manipulated to achieve increased or decreased pI values (cationization or anionization, respectively). Since the surface of most cells is negatively charged, antibodies need to be positively charged for efficient fluid-phase endocytosis (pinocytosis), therefore the environmental pH needs to be below the pI of the antibody. When assessing pharmacokinetic (PK) properties of therapeutic antibodies not only the target-mediated drug disposition (TMDD) but also non-target-related mechanisms influence overall PK behavior and pI can be an important factor of the latter. If the pH of the surrounding environment is below the antibody’s pI, then the molecule carries a net positive charge, whereas the antibody will carry a net negative charge when the pH is above the pI. One important characteristic of monoclonal antibodies (mAbs) is their isoelectric point (pI), which essentially is the pH at which the antibody has no net electrical charge, and its value depends on the charged amino acids the antibody contains. Meeting Report: The Diagnostic Landscape for COVID-19.Guide to “Coronavirus in the Crosshairs”.Snakebite antivenoms: Global challenges and progress toward recombinant antibody therapeutics.Antibodies in late-stage clinical studies.Antibody therapeutics approved or in regulatory review in the EU or US.Huston Antibody Science Talent Award Recipient AIRR Community Meeting IV: “Bridging the Gaps”.AIRR Community Special Event: “Response to COVID-19”.AIRR-seq Biological Standards and Workflows.AIRR Community Meeting V: “Zooming in to the AIRR Community”.AIRR Community Meeting VI: “Exploring New Frontiers”.
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