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    Quantitative Correlation of in Vivo Properties with in Vitro Assay Results: The in Vitro Binding of a Biotin-DNA Analogue Modifier with Streptavidin Predicts the in Vivo Avidin-Induced Clearability of the Analogue-Modified Antibody

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    Authors
    Dou, Shuping
    Virostko, John
    Greiner, Dale L.
    Powers, Alvin C.
    Liu, Guozheng
    UMass Chan Affiliations
    Program in Molecular Medicine
    Department of Radiology
    Document Type
    Journal Article
    Publication Date
    2015-08-03
    Keywords
    antibody conjugate
    clearance
    in vitro assay
    in vivo properties
    morpholino oligomers
    quantitative correlation
    trifunctional antibody
    Biochemistry
    Medicinal and Pharmaceutical Chemistry
    Medicinal-Pharmaceutical Chemistry
    
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    Link to Full Text
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711347/
    Abstract
    Quantitative prediction of in vivo behavior using an in vitro assay would dramatically accelerate pharmaceutical development. However, studies quantitatively correlating in vivo properties with in vitro assay results are rare because of the difficulty in quantitatively understanding the in vivo behavior of an agent. We now demonstrate such a correlation as a case study based on our quantitative understanding of the in vivo chemistry. In an ongoing pretargeting project, we designed a trifunctional antibody (Ab) that concomitantly carried a biotin and a DNA analogue (hereafter termed MORF). The biotin and the MORF were fused into one structure prior to conjugation to the Ab for the concomitant attachment. Because it was known that avidin-bound Ab molecules leave the circulation rapidly, this design would theoretically allow complete clearance by avidin. The clearability of the trifunctional Ab was determined by calculating the blood MORF concentration ratio of avidin-treated Ab to non-avidin-treated Ab using mice injected with these compounds. In theory, any compromised clearability should be due to the presence of impurities. In vitro, we measured the biotinylated percentage of the Ab-reacting (MORF-biotin) superset-NH2 modifier, by addition of streptavidin to the radiolabeled (MORF-biotin) superset-NH2 samples and subsequent high-performance liquid chromatography (HPLC) analysis. On the basis of our previous quantitative understanding, we predicted that the clearability of the Ab would be equal to the biotinylation percentage measured via HPLC. We validated this prediction within a 3% difference. In addition to the high avidin-induced clearability of the trifunctional Ab (up to approximately 95%) achieved by the design, we were able to predict the required quality of the (MORF-biotin) superset-NH2 modifier for any given in vivo clearability. This approach may greatly reduce the steps and time currently required in pharmaceutical development in the process of synthesis, chemical analysis, in vitro cell study, and in vivo validation.
    Source
    Mol Pharm. 2015 Aug 3;12(8):3097-103. doi: 10.1021/mp5008579. Epub 2015 Jul 8. Link to article on publisher's site
    DOI
    10.1021/mp5008579
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/39887
    PubMed ID
    26103429
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1021/mp5008579
    Scopus Count
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    UMass Chan Faculty and Researcher Publications
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