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

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 24; pp. 6929 - 6939
• Main Authors: Vaidyanathan, G., White, B.J., Affleck, D.J., Zhao, X.G., Welsh, P.C., McDougald, D., Choi, J., Zalutsky, M.R.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2012; Elsevier
• Subjects: Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacokinetics; Biochemistry & Molecular Biology; Biological and medical sciences; Catabolites; Cell Line, Tumor; chelating agents; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Glioblastoma - immunology; Glioblastoma - metabolism; Heterocyclic Compounds, 1-Ring - chemical synthesis; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - pharmacokinetics; Humans; Immunotoxins - chemistry; Immunotoxins - pharmacokinetics; Internalization; Iodine Radioisotopes - chemistry; Iodine Radioisotopes - pharmacokinetics; Iodobenzoates - chemical synthesis; Iodobenzoates - chemistry; Iodobenzoates - pharmacokinetics; Isotope Labeling - methods; Life Sciences & Biomedicine; Medical sciences; Mice; Mice, Inbred BALB C; monoclonal antibodies; Monoclonal antibody; Organometallic Compounds - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; prostheses; Radioiodine; radiolabeling; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - immunology; Radiopharmaceuticals - pharmacokinetics; Receptor, Epidermal Growth Factor - immunology; Residualizing labels; Science & Technology; tin; Tin - chemistry; Tissue Distribution; Radioiodine; Monoclonal antibody; Residualizing labels; Internalization; AGENT; RADIOIODINATION; THERAPY; COMPLEXES; IODOBENZOATE; N-SUCCINIMIDYL; CELLULAR RETENTION; BINDING; Radiolabelling; Nitrogen crown compound; Prosthetic group; Iodine Isotopes; Malignant tumor; Uptake; Labelled compound; Cancer
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.10.025

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 [131I]SIB-DOTA in 27.1±6.2% (n=2) conjugation yields and its targeting properties to the same mAb labeled with [125I]SGMIB both in vitro and in vivo using U87MG·ΔEGFR cells and xenografts were compared. In vitro paired-label internalization assays showed that the intracellular radioactivity from [131I]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 [125I]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.