Influence of antibody Fab charge, hydrophobicity, and hydrodynamic size on vitreous pharmacokinetics in rabbits
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Issue Date
2017-12-31Author
Wang, Yue
Publisher
University of Kansas
Format
46 pages
Type
Thesis
Degree Level
M.S.
Discipline
Pharmaceutical Chemistry
Rights
Copyright held by the author.
Metadata
Show full item recordAbstract
A better understanding of the molecular attributes contributing to vitreal elimination half-life could enable the design of improved therapeutics for the treatment of human posterior segment ocular disease. Here we have used pharmacokinetics (PK) studies in rabbits to probe the contribution of electrostatic charge, hydrophobicity, and hydrodynamic size to vitreal clearance of antibody fragments (Fabs). Comparing Fabs of diverse binding targets, we find that vitreal half-life is not strongly correlated with measured isoelectric point (pI) or the hydrophobicity index (HI) of the variable domain unit (Fv) calculated from the amino acid sequence. We completed two systematic studies of molecule charge and hydrophobicity by determining the vitreal half-life of variants of ranibizumab. Charge or hydrophobicity was altered through introduction of amino acid changes in two of the hypervariable regions of the light chain. Equivalent vitreal pharmacokinetics were observed for ranibizumab and these variants with pIs in the range 6.8 – 10.2 and Fv HI varied in the range 1090-1296. Finally, a previously observed linear dependence between vitreal half-life and hydrodynamic radius, determined using light scattering measurements, has been extended to a broader range. These results indicate that diffusive properties of antibody Fabs, as quantified by the hydrodynamic radius, make a key contribution to vitreal elimination whereas minor or negligible contributions arise from differences in charge or hydrophobicity in the ranges tested in these studies.
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- Pharmaceutical Chemistry Dissertations and Theses [141]
- Theses [3944]
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