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

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Goodwin, D. A. Articles by Osen, M. Search for Related Content PubMed PubMed Citation Articles by Goodwin, D. A. Articles by Osen, M.

Biological Properties of Biotin—Chelate Conjugates for Pretargeted Diagnosis and Therapy with the Avidin/Biotin System

Department of Nuclear Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto; Department of Radiology, Stanford University, Stanford; Department of Chemistry, University of Cahfornia, Davis, California

Correspondence: For correspondence or reprints contact: David A. Goodwin, MD, Department of Nuclear Medicine, veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA 94304.

ABSTRACT

Three-step pretargeting increases target-to-background ratios in radioimmunodetection and can potentially decrease harmful radiation to normal tissues in radioimmunotherapy. We studied four biotin–chelateconjugates (BCCs) for use in the avidin/biotin pretargeting system. Methods: Pharmacokinetics and biodistribution were studied in normal BALB/c (IA^k-negative),normal C3H (IA^k-positive) and LS174T tumor-bearing BALB/c severe combined immunodeficient mice. Streptavidin alone and antibody–streptavidin conjugates[monoclonal anthody(MAb)10-3.6 anti-IA^k IgG2a] were used. Indium-111- or ⁸⁸Y-BCCs were given alone intravenously; they were mixed with streptavidin or MAb-streptavidin conjugate and given intravenously; or streptavidin and MAb-streptavidin conjugate were pretargeted, and 2–3, 5 and 21 hr later, BCCs were injected intravenously. Samples were taken 2-3 hr after intravenous injection of labeled BCCs. Results: Three of the four BCCs were rapidly excreted by the kidneys, with <2.5%/g in any organ or tumor at 2–3hr. Gut excretion eliminated biotinyl-(S)-1-p-aminobenzylethylenediaminetetraacetic acid (EDTA) for use in pretargeting. Ninety percent of BCCs were bound to circulating pretargeted streptavidin at 1–6 hr, and 15% were bound to pretargeted streptavidin at 24 hr. Kidney uptakes were: preformed streptavidin BCC given intravenously,80%/g(24 hr); streptavidin pretargeted for 2–3hr, 60%/g; and streptavidin pretargeted for 5–21 hr, 10%–20%/g. Kidney uptake was dose-dependent: 0.2, 0.67 and 1.0 nmol of streptavrdin pretargeted for 21 hr showed increasing concentrations (24 hr. Uptake of monoclonal anti-IA^k streptavidin BCC complex into spleen (70% ± 10%/g; p < 0.05) and lymph nodes (10% ± 3.5%/g; p < 0.01) was higher in IA^k positive C₃H mice than it was in IA^k-negative control BALB/c mice, and it was much higher than that in streptavidin controls. No significant target uptake was seen with anti-IA^k MAb-streptavidin pretargeted for 3 or 0 hr. Kidney uptake 20%/g, which was lower than that of streptavidin alone. Conclusion: Three biotinyl chelates bind the diagnostic and therapeutic radiometals ¹¹¹In and ⁸⁸Y (and, by analogy, ⁹⁰Y) with the required in vivo stability and physiological properties for pretargeted diagnosis and therapy. Kidney uptake of streptavidin was decreased by conjugation to MAb. Failure of anti-IA^k MAb-streptavidin conjugate to bind BCC after pretargeting may be due to rapid internalization of MAb–streptavidin-IA^k complex by the lymphocyte or to endogenous biotin. Either or both of these would make streptavidin unavailable to subsequent BCCs.

Key Words: radioimmunoimaging • radioimmunotherapy • yttrium-90 • indium-111 • pretargeting

This article has been cited by other articles:

				D. J. Green, J. M. Pagel, A. Pantelias, N. Hedin, Y. Lin, D. S. Wilbur, A. Gopal, D. K. Hamlin, and O. W. Press Pretargeted Radioimmunotherapy for B-Cell Lymphomas Clin. Cancer Res., September 15, 2007; 13(18): 5598s - 5603s. [Abstract] [Full Text] [PDF]

				J. M. Pagel, A. Pantelias, N. Hedin, S. Wilbur, L. Saganic, Y. Lin, D. Axworthy, D. K. Hamlin, D. S. Wilbur, A. K. Gopal, et al. Evaluation of CD20, CD22, and HLA-DR Targeting for Radioimmunotherapy of B-Cell Lymphomas Cancer Res., June 15, 2007; 67(12): 5921 - 5928. [Abstract] [Full Text] [PDF]

				A. Pantelias, J. M. Pagel, N. Hedin, L. Saganic, S. Wilbur, D. K. Hamlin, D. S. Wilbur, Y. Lin, D. Stone, D. Axworthy, et al. Comparative biodistributions of pretargeted radioimmunoconjugates targeting CD20, CD22, and DR molecules on human B-cell lymphomas Blood, June 1, 2007; 109(11): 4980 - 4987. [Abstract] [Full Text] [PDF]

				J. M. Pagel, Y. Lin, N. Hedin, A. Pantelias, D. Axworthy, D. Stone, D. K. Hamlin, D. S. Wilbur, and O. W. Press Comparison of a tetravalent single-chain antibody-streptavidin fusion protein and an antibody-streptavidin chemical conjugate for pretargeted anti-CD20 radioimmunotherapy of B-cell lymphomas Blood, July 1, 2006; 108(1): 328 - 336. [Abstract] [Full Text] [PDF]

				Y. Lin, J. M. Pagel, D. Axworthy, A. Pantelias, N. Hedin, and O. W. Press A Genetically Engineered Anti-CD45 Single-Chain Antibody-Streptavidin Fusion Protein for Pretargeted Radioimmunotherapy of Hematologic Malignancies. Cancer Res., April 1, 2006; 66(7): 3884 - 3892. [Abstract] [Full Text] [PDF]

				D. M. Goldenberg, R. M. Sharkey, G. Paganelli, J. Barbet, and J.-F. Chatal Antibody Pretargeting Advances Cancer Radioimmunodetection and Radioimmunotherapy J. Clin. Oncol., February 10, 2006; 24(5): 823 - 834. [Abstract] [Full Text] [PDF]

				A. Forero, P. L. Weiden, J. M. Vose, S. J. Knox, A. F. LoBuglio, J. Hankins, M. L. Goris, V. J. Picozzi, D. B. Axworthy, H. B. Breitz, et al. Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma Blood, July 1, 2004; 104(1): 227 - 236. [Abstract] [Full Text] [PDF]

				O. W. Press, M. Corcoran, K. Subbiah, D. K. Hamlin, D. S. Wilbur, T. Johnson, L. Theodore, E. Yau, R. Mallett, D. L. Meyer, et al. A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts Blood, October 15, 2001; 98(8): 2535 - 2543. [Abstract] [Full Text] [PDF]

				R. Weissleder and U. Mahmood Molecular Imaging Radiology, May 1, 2001; 219(2): 316 - 333. [Abstract] [Full Text]

				S. P. Lubic, D. A. Goodwin, C. F. Meares, C. Song, M. Osen, and M. Hays Biodistribution and Dosimetry of Pretargeted Monoclonal Antibody 2D12.5 and Y-Janus-DOTA in BALB/c Mice with KHJJ Mouse Adenocarcinoma J. Nucl. Med., April 1, 2001; 42(4): 670 - 678. [Abstract] [Full Text]