HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Supplemental Data All Versions of this Article: jnumed.108.055608v1 50/3/435    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schneider, D. W. Articles by Parry, R. Search for Related Content PubMed PubMed Citation Articles by Schneider, D. W. Articles by Parry, R.

In Vivo Biodistribution, PET Imaging, and Tumor Accumulation of ⁸⁶Y- and ¹¹¹In-Antimindin/RG-1, Engineered Antibody Fragments in LNCaP Tumor–Bearing Nude Mice

¹ Cancer Research, Berlex Biosciences/Schering AG, Richmond, California; ² Antibody Technology, Berlex Biosciences/Schering AG, Richmond, California; ³ Pharmacology, Berlex Biosciences/Schering AG, Richmond, California; and ⁴ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri

Correspondence: For correspondence or reprints contact: Douglas W. Schneider, Molecular and Antibody Biology, Bayer Healthcare Pharmaceuticals, 2600 Hilltop Dr., Richmond, CA 94804. E-mail: doug.schneider{at}bayer.com

To optimize in vivo tissue uptake kinetics and clearance of engineered monoclonal antibody (mAb) fragments for radiotherapeutic and radiodiagnostic applications, we compared the biodistribution and tumor localization of four ¹¹¹In- and ⁸⁶Y-labeled antibody formats, derived from a single antimindin/RG-1 mAb, in a prostate tumor model. The IgG, diabody, single-chain variable domain (scFv), and novel miniantibody formats, composed of the human IgE-C_H4 and a modified IgG1 hinge linked to scFv domains, were compared. Methods: Antibodies were first derivatized with the bifunctional chelator CHX-A''-diethylenetriamine pentaacetic acid and then bound to the radiometal to create radiolabeled immunoconjugates. Human LNCaP xenografts were grown in nude mice, and ¹¹¹In- or ⁸⁶Y-labeled antibodies were administered intravenously. Tissues were harvested at different times, and the level of antibody deposition was determined by measuring radioactivity. Whole-body small-animal PET of mice receiving ⁸⁶Y-labeled antibodies was performed at 6 time points and colocalized with simultaneous micro-CT imaging. Results: The biodistributions of ¹¹¹In and ⁸⁶Y antibodies were quite similar. The blood, tumor, kidney, and liver tissues contained varying levels of radioactivity. The antibody accumulation in the tumor correlated with molecular size. The IgG steadily increased with time to 24.1 percentage injected dose per gram (%ID/g) at 48 h. The miniantibody accumulated at a similar rate to reach a lower level (14.2 %ID/g) at 48 h but with a higher tumor-to-blood ratio than the IgG. Tumor accumulation of the diabody peaked at 3 h, reaching a much lower level (3.7 %ID/g). A combination of rapid clearance and lower relative affinity of the scFv precluded deposition in the tumor. Small-animal PET results correlated well with the biodistribution results, with similar tumor localization patterns. Conclusion: The larger antibody formats (IgG and miniantibody) gave higher tumor uptake levels than did the smaller formats (diabody and scFv). These larger formats may be more suitable for radioimmunotherapy applications, evidenced by the preclinical efficacy previously shown by a report on the IgG format. The smaller formats were rapidly cleared from circulation, and the diabody, which accumulated in the tumor, may be more suitable for radiodiagnostic applications.

Key Words: ⁸⁶Y PET • ¹¹¹In biodistribution • mindin • RG-1 • IgE-C_H4 miniantibody

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

Related articles in JNM:

This Month in JNM

JNM 2009 50: 11A-12A. [Full Text]  

This article has been cited by other articles:

				K. D. Orcutt, M. E. Ackerman, M. Cieslewicz, E. Quiroz, A. L. Slusarczyk, J. V. Frangioni, and K. D. Wittrup A modular IgG-scFv bispecific antibody topology Protein Eng. Des. Sel., December 17, 2009; (2009) gzp077v1. [Abstract] [Full Text] [PDF]