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    Influence of antibody Fab charge, hydrophobicity, and hydrodynamic size on vitreous pharmacokinetics in rabbits

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    Wang_ku_0099M_15609_DATA_1.pdf (1.817Mb)
    Issue Date
    2017-12-31
    Author
    Wang, Yue
    Publisher
    University of Kansas
    Format
    46 pages
    Type
    Thesis
    Degree Level
    M.S.
    Discipline
    Pharmaceutical Chemistry
    Rights
    Copyright held by the author.
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    Abstract
    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.
    URI
    http://hdl.handle.net/1808/26162
    Collections
    • Pharmaceutical Chemistry Dissertations and Theses [141]
    • Theses [3797]

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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