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.
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Authors | G Vaidyanathan, B J White, D J Affleck, X G Zhao, P C Welsh, D McDougald, J Choi, M R Zalutsky |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 20
Issue 24
Pg. 6929-39
(Dec 15 2012)
ISSN: 1464-3391 [Electronic] England |
PMID | 23159039
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 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
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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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