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Preclinical Development

Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model

Cinthia V. Pastuskovas, Eduardo E. Mundo, Simon P. Williams, Tapan K. Nayak, Jason Ho, Sheila Ulufatu, Suzanna Clark, Sarajane Ross, Eric Cheng, Kathryn Parsons-Reponte, Gary Cain, Marjie Van Hoy, Nicholas Majidy, Sheila Bheddah, Josefa dela Cruz Chuh, Katherine R. Kozak, Nicholas Lewin-Koh, Peter Nauka, Daniela Bumbaca, Mark Sliwkowski, Jay Tibbitts, Frank-Peter Theil, Paul J. Fielder, Leslie A. Khawli and C. Andrew Boswell
Cinthia V. Pastuskovas
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Eduardo E. Mundo
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Simon P. Williams
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Tapan K. Nayak
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Jason Ho
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Sheila Ulufatu
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Suzanna Clark
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Sarajane Ross
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Eric Cheng
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Kathryn Parsons-Reponte
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Gary Cain
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Marjie Van Hoy
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Nicholas Majidy
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Sheila Bheddah
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Josefa dela Cruz Chuh
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Katherine R. Kozak
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Nicholas Lewin-Koh
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Peter Nauka
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Daniela Bumbaca
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Mark Sliwkowski
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Jay Tibbitts
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Frank-Peter Theil
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Paul J. Fielder
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Leslie A. Khawli
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C. Andrew Boswell
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DOI: 10.1158/1535-7163.MCT-11-0742-T Published March 2012
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    Figure 1.

    Blood pharmacokinetic curves of 125I-labeled (A) and 111In-labeled (B) antibodies at various doses through 7 days. Solid data symbols correspond to control mice, whereas open symbols indicate mice treated with anti-VEGF at 24 hours before tracer administration.

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    Figure 2.

    Tumor pharmacokinetic curves with and without anti-VEGF (B20.4.1) pretreatment: trastuzumab at doses of 0.1 mg/kg (A), 1.4 mg/kg (B), 17 mg/kg (C), and a control IgG at a dose of 18 mg/kg (D).

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    Figure 3.

    Tissue distribution of 111In-labeled (A and B) and 125I-labeled (C and D) antibodies at 120-hour postinjection. Data in B and D are derived from mice receiving anti-VEGF at 24 hours before tracer injection.

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    Figure 4.

    Absolute difference in AUC (%ID/g × d), relative to control, due to the effect of a 24-hour pretreatment of the anti-VEGF antibody, B20-4.1.

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    Figure 5.

    SPECT-CT (A–D) and autoradiograms with their respective pseudocolor heat map (E and F) imaging data acquired in mice following intravenous administration of 111In-trastuzumab. For SPECT-CT images, 3-dimensional volume renderings from a coronal perspective (top), coronal tomographic slices (middle), and axial tomographic slices (bottom) are displayed. Mice received 111In-trastuzumab tracer only (A and C) or were coinjected with a dose of 14 to 17 mg/kg (B, D–F). Only mice in C, D, and F received a single intravenous dose of anti-VEGF (10 mg/kg) at 24 hours before tracer injection.

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    Figure 6.

    Immunohistochemical staining of KPL-4 tumor sections for the MECA-32 vascular endothelium marker (brown; A, B), HER2 receptors (pink; C, D), and bound trastuzumab (blue; E, F). Images in A, C, and E correspond to trastuzumab (17 mg/kg) only treated mice, whereas those in B, D, and F are derived from mice receiving a single anti-VEGF dose (10 mg/kg) 24 hours before trastuzumab. Tumors were harvested at 24 hours after intravenous administration of trastuzumab. Scale bar, 500 μm. Insets display same tumor sections at a larger scale (2.0 mm).

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Molecular Cancer Therapeutics: 11 (3)
March 2012
Volume 11, Issue 3
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Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model
Cinthia V. Pastuskovas, Eduardo E. Mundo, Simon P. Williams, Tapan K. Nayak, Jason Ho, Sheila Ulufatu, Suzanna Clark, Sarajane Ross, Eric Cheng, Kathryn Parsons-Reponte, Gary Cain, Marjie Van Hoy, Nicholas Majidy, Sheila Bheddah, Josefa dela Cruz Chuh, Katherine R. Kozak, Nicholas Lewin-Koh, Peter Nauka, Daniela Bumbaca, Mark Sliwkowski, Jay Tibbitts, Frank-Peter Theil, Paul J. Fielder, Leslie A. Khawli and C. Andrew Boswell
Mol Cancer Ther March 1 2012 (11) (3) 752-762; DOI: 10.1158/1535-7163.MCT-11-0742-T

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Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model
Cinthia V. Pastuskovas, Eduardo E. Mundo, Simon P. Williams, Tapan K. Nayak, Jason Ho, Sheila Ulufatu, Suzanna Clark, Sarajane Ross, Eric Cheng, Kathryn Parsons-Reponte, Gary Cain, Marjie Van Hoy, Nicholas Majidy, Sheila Bheddah, Josefa dela Cruz Chuh, Katherine R. Kozak, Nicholas Lewin-Koh, Peter Nauka, Daniela Bumbaca, Mark Sliwkowski, Jay Tibbitts, Frank-Peter Theil, Paul J. Fielder, Leslie A. Khawli and C. Andrew Boswell
Mol Cancer Ther March 1 2012 (11) (3) 752-762; DOI: 10.1158/1535-7163.MCT-11-0742-T
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