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SIB-DOTA: a trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies.

Abstract
A major drawback of internalizing monoclonal antibodies (mAbs) radioiodinated with direct electrophilic approaches is that tumor retention of radioactivity is compromised by the rapid washout of iodo-tyrosine, the primary labeled catabolite for mAbs labeled via this strategy. In our continuing efforts to develop more versatile residualizing labels that could overcome this problem, we have designed SIB-DOTA, a prosthetic labeling template that combines the features of the prototypical, dehalogenation-resistant N-succinimidyl 3-iodobenzoate (SIB) with DOTA, a useful macrocyclic chelator for labeling with radiometals. Herein we describe the synthesis of the unlabeled standard of this prosthetic moiety, its protected tin precursor, and radioiodinated SIB-DOTA. An anti-EGFRvIII-reactive mAb, L8A4 was radiolabeled with [(131)I]SIB-DOTA in 27.1±6.2% (n=2) conjugation yields and its targeting properties to the same mAb labeled with [(125)I]SGMIB both in vitro and in vivo using U87MG·Î”EGFR cells and xenografts were compared. In vitro paired-label internalization assays showed that the intracellular radioactivity from [(131)I]SIB-DOTA-L8A4 was 21.4±0.5% and 26.2±1.1% of initially bound radioactivity at 16 and 24h, respectively. In comparison, these values for [(125)I]SGMIB-L8A4 were 16.7±0.5% and 14.9±1.1%. Similarly, the SIB-DOTA prosthetic group provided better tumor targeting in vivo than SGMIB over 8 d period. These results suggest that SIB-DOTA warrants further evaluation as a residualizing agent for labeling internalizing mAbs including those targeted to EGFRvIII.
AuthorsG Vaidyanathan, B J White, D J Affleck, X G Zhao, P C Welsh, D McDougald, J Choi, M R Zalutsky
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 24 Pg. 6929-39 (Dec 15 2012) ISSN: 1464-3391 [Electronic] England
PMID23159039 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Antibodies, Monoclonal
  • Heterocyclic Compounds, 1-Ring
  • Immunotoxins
  • Iodine Radioisotopes
  • Iodobenzoates
  • Organometallic Compounds
  • Radiopharmaceuticals
  • epidermal growth factor receptor VIII
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • Tin
  • N-succinimidyl 3-iodobenzoate
  • ErbB Receptors
Topics
  • Animals
  • Antibodies, Monoclonal (chemistry, immunology, pharmacokinetics)
  • Cell Line, Tumor
  • ErbB Receptors (immunology)
  • Glioblastoma (immunology, metabolism)
  • Heterocyclic Compounds, 1-Ring (chemical synthesis, chemistry, pharmacokinetics)
  • Humans
  • Immunotoxins (chemistry, pharmacokinetics)
  • Iodine Radioisotopes (chemistry, pharmacokinetics)
  • Iodobenzoates (chemical synthesis, chemistry, pharmacokinetics)
  • Isotope Labeling (methods)
  • Mice
  • Mice, Inbred BALB C
  • Organometallic Compounds (chemistry)
  • Radiopharmaceuticals (chemical synthesis, chemistry, immunology, pharmacokinetics)
  • Tin (chemistry)
  • Tissue Distribution

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