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Research ArticleArticle

Effect of Immune Complex Formation on the Distribution of a Novel Antibody to the Ovarian Tumor Antigen CA125

Cinthia V. Pastuskovas, William Mallet, Suzanna Clark, Margaret Kenrick, Mohammed Majidy, Michelle Schweiger, Marjie Van Hoy, Siao Ping Tsai, Gregory Bennett, Ben-Quan Shen, Sarajane Ross, Paul Fielder, Leslie Khawli and Jay Tibbitts
Drug Metabolism and Disposition December 2010, 38 (12) 2309-2319; DOI: https://doi.org/10.1124/dmd.110.034330
Cinthia V. Pastuskovas
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William Mallet
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Suzanna Clark
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Margaret Kenrick
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Mohammed Majidy
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Michelle Schweiger
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Marjie Van Hoy
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Siao Ping Tsai
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Gregory Bennett
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Ben-Quan Shen
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Sarajane Ross
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Paul Fielder
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Leslie Khawli
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Jay Tibbitts
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Abstract

3A5 is a novel antibody that binds repeated epitopes within CA125, an ovarian tumor antigen that is shed into the circulation. Binding to shed antigen may limit the effectiveness of therapeutic antibodies because of unproductive immune complex (IC) formation and/or altered antibody distribution. To evaluate this possibility, we characterized the impact of shed CA125 on the in vivo distribution of 3A5. In vitro, 3A5 and CA125 were found to form ICs in a concentration-dependent manner. This phenomenon was then evaluated in vivo using quantitative whole-body autoradiography to assess the tissue distribution of 125I-3A5 in an orthotopic OVCAR-3 tumor mouse model at different stages of tumor burden. Low doses of 3A5 (75 μg/kg) and pathophysiological levels of shed CA125 led to the formation of ICs in vivo that were rapidly distributed to the liver. Under these conditions, increased clearance of 3A5 from normal tissues was observed in mice bearing CA125-expressing tumors. Of importance, despite IC formation, 3A5 uptake by tumors was sustained over time. At a therapeutically relevant dose of 3A5 (3.5 mg/kg), IC formation was undetectable and distribution to normal tissues followed that of blood. In contrast, increased levels of radioactivity were observed in the tumors. These data demonstrate that CA125 and 3A5 do form ICs in vivo and that the liver is involved in their uptake. However, at therapeutic doses of 3A5 and clinically relevant CA125 levels, IC formation consumes only a minor fraction of 3A5, and tumor targeting seems to be unaffected.

Footnotes

  • This work was supported by Genentech, Inc.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.034330.

  • ABBREVIATIONS:

    IC
    immune-complex
    luc
    luciferase-expressing
    QWBA
    quantitative whole-body autoradiography
    TCA
    trichloroacetic acid
    PBS
    phosphate-buffered saline
    SEC-HPLC
    size exclusion high-performance liquid chromatography
    %ID/g
    percentage of injected dose normalized to a gram of tissue
    ELISA
    enzyme-linked immunosorbent assay.

  • Received May 6, 2010.
  • Accepted September 7, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Research ArticleArticle

Effect of Immune Complex Formation on the Distribution of a Novel Antibody to the Ovarian Tumor Antigen CA125

Cinthia V. Pastuskovas, William Mallet, Suzanna Clark, Margaret Kenrick, Mohammed Majidy, Michelle Schweiger, Marjie Van Hoy, Siao Ping Tsai, Gregory Bennett, Ben-Quan Shen, Sarajane Ross, Paul Fielder, Leslie Khawli and Jay Tibbitts
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2309-2319; DOI: https://doi.org/10.1124/dmd.110.034330

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Research ArticleArticle

Effect of Immune Complex Formation on the Distribution of a Novel Antibody to the Ovarian Tumor Antigen CA125

Cinthia V. Pastuskovas, William Mallet, Suzanna Clark, Margaret Kenrick, Mohammed Majidy, Michelle Schweiger, Marjie Van Hoy, Siao Ping Tsai, Gregory Bennett, Ben-Quan Shen, Sarajane Ross, Paul Fielder, Leslie Khawli and Jay Tibbitts
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2309-2319; DOI: https://doi.org/10.1124/dmd.110.034330
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