Pretargeted radioimmunotherapy with a single-chain antibody/streptavidin construct and radiolabeled DOTA-biotin: Strategies for reduction of the renal dose Journal Article

  

Authors:	Forster, G. J.; Santos, E. B.; Smith-Jones, P. M.; Zanzonico, P.; Larson, S. M.
Article Title:	Pretargeted radioimmunotherapy with a single-chain antibody/streptavidin construct and radiolabeled DOTA-biotin: Strategies for reduction of the renal dose
Abstract:	Multistep immune targeting holds great promise for radio-immunodiagnosis and therapy of cancer. Pretargeting of the tetrameric single-chain, variable-fragment streptavidin construct of the tetrameric monoclonal antibody CC49 with subsequent administration of radiolabeled 1,4,7,10- tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-biotin has yielded promising results in TAG-72-expressing tumor xenograft models. A potential limitation of this approach, however, has been high and prolonged renal uptake of radioactivity. The objective of the current study, therefore, was to evaluate the reduction of kidney uptake of radiolabeled DOTA-biotin achieved by each of 4 different methods. Methods: A human pancreatic adenocarcinoma xenograft model (HPAC) in nude mice was used. The animals were intravenously injected with the antibody-streptavidin construct and a synthetic clearing agent (biotinylated N-acetylgalactosamine) 24 and 4 h, respectively, before the administration of 67Ga-DOTA-biotin. For reduction of the renal uptake, different groups of mice were treated with streptavidin saturated with biotin, with several administrations of lysine or colchicine or with a succinylated antibody-streptavidin construct (resulting in a decreased electrical charge). All animals were sacrificed 24 h after injection of the 67Ga-DOTA-biotin for biodistribution and quantitative autoradiography (QAR) studies and selected animals underwent microSPECT/microCT studies. Results: There was marked targeting of the radiolabeled DOTA-biotin to tumor in all groups except in negative-control animals. Only succinylation of the scFv-CC49-streptavidin fusion protein significantly reduced (∼30%) kidney uptake without affecting tumor activity. QAR corroborated these results and demonstrated that radiolabeled DOTA-biotin localized selectively in the renal cortex. Among the other experimental groups, there was no change in kidney uptake of the radiolabeled biotin. Conclusion: In contrast to directly labeled antibodies and antibody fragments, administration of the negatively charged amino acid lysine was largely ineffective in pretargeting strategies with a single-chain-immunostreptavidin fusion protein. Succinylation of the scFv-CC49-streptavidin construct, on the other hand, reduces kidney uptake of subsequently administered radiolabeled biotin, presumably by inhibiting reuptake of the fusion protein in the proximal renal tubules, and, therefore, could significantly reduce renal doses and improve therapeutic indices associated with multistep immune targeting approaches to radioimmunotherapy.
Keywords:	controlled study; unclassified drug; nonhuman; radiation dose; methodology; radiopharmaceuticals; adenocarcinoma; mouse; animal; metabolism; animals; mice; radiotherapy dosage; animal experiment; animal model; in vivo study; monoclonal antibody; drug delivery systems; kidney; immunoglobulin fragment; hybrid protein; drug distribution; isotope labeling; nude mouse; tissue distribution; mice, nude; evaluation; three dimensional imaging; organ specificity; radiopharmaceutical agent; drug derivative; scintiscanning; pancreas adenocarcinoma; antibody specificity; metabolic clearance rate; micro-computed tomography; radioisotope; radioimmunotherapy; whole body counting; whole-body counting; single photon emission computer tomography; organometallic compound; organometallic compounds; single chain fragment variable antibody; streptavidin; autoradiography; lysine; drug delivery system; colchicine; biotin; kidney cortex; immunoglobulin fragments; gallium; kidney tubule absorption; kidney dosimetry; microspect; multistep-targeting/pretargeting; quantitative autoradiography; scfv-cc49-streptavidin- immune construct; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid biotin gallium 67; cc49 antibody; dota biotin; dota-biotin; gallium radioisotopes
Journal Title:	Journal of Nuclear Medicine
Volume:	47
Issue:	1
ISSN:	0161-5505
Publisher:	Society of Nuclear Medicine
Date Published:	2006-01-01
Start Page:	140
End Page:	149
Language:	English
PUBMED:	16391198
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-33744938982&partnerID=40&md5=f70aea97a9da0506d8f1da0b9ecde7ff
Notes:	--- - "Cited By (since 1996): 27" - "Export Date: 4 June 2012" - "CODEN: JNMEA" - "Source: Scopus"

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