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| - Nε-(3-[*I]Iodobenzoyl)-Lys5-Nα-maleimido-Gly1-GEEEK ([*I]IB-Mal-d-GEEEK): A Radioiodinated Prosthetic Group Containing Negatively Charged d-Glutamatesfor Labeling Internalizing Monoclonal Antibodies
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| - Novel methods are needed for the radiohalogenation of cell-internalizing proteins and peptides because rapid lossof label occurs after lysosomal processing when these molecules are labeled using conventional radioiodinationmethodologies. We have developed a radiolabeled prosthetic group that contains multiple negatively chargedd-amino acids to facilitate trapping of the radioactivity in the cell after proteolysis of the labeled protein. Nε-(3-[125I]iodobenzoyl)-Lys5-Nα-maleimido-Gly1-GEEEK ([125I]IB-Mal-d-GEEEK) was synthesized via iododestannylation in 90.3 ± 3.9% radiochemical yields. This radioiodinated agent was conjugated to iminothiolane-treated L8A4, an anti-epidermal growth factor receptor variant III (EGFRvIII) specific monoclonal antibody (mAb)in 54.3 ± 17.7% conjugation yields. In vitro assays with the EGFRvIII-expressing U87MGΔEGFR glioma cellline demonstrated that the internalized radioactivity for the [125I]IB-Mal-d-GEEEK-L8A4 conjugate increasedfrom 14.1% at 1 h to 44.7% at 24 h and was about 15-fold higher than that of directly radioiodinated L8A4 at24 h. A commensurately increased tumor uptake in vivo in athymic mice bearing subcutaneous U87MGΔEGFRxenografts (52.6 ± 14.3% injected dose per gram versus 17.4 ± 3.5% ID/g at 72 h) also was observed. Theseresults suggest that [125I]IB-Mal-d-GEEEK is a promising reagent for the radioiodination of internalizing mAbs.
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