A Polar Substituent-Containing Acylation Agent for the Radioiodination of Internalizing Monoclonal Antibodies: N-Succinimidyl 4-Guanidinomethyl-3-[131I]iodobenzoate ([131I

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• 作者：Ganesan Vaidyanathan ; Donna J. Affleck ; Jean Li ; Phil Welsh ; and Michael R. Zalutsky
• 刊名：Bioconjugate Chemistry
• 出版年：2001
• 出版时间：May 2001
• 年：2001
• 卷：12
• 期：3
• 页码：428 - 438
• 全文大小：132K
• 年卷期：v.12,no.3(May 2001)
• ISSN：1520-4812

文摘

The objective of this study was to develop an acylation agent for the radioiodination of monoclonalantibodies that would maximize retention of the label in tumor cells following receptor- or antigen-mediated internalization. The strategy taken was to add a polar substituent to the labeled aromaticring to impede transport of labeled catabolites across lysosomal and cell membranes after antibodydegradation. Preparation of unlabeled N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB) wasachieved in six steps from 3-iodo-4-methylbenzoic acid. Preparation of 4-guanidinomethyl-3-[¹³¹I]iodobenzoic acid from the silicon precursor, 4-(N¹,N²-bis-tert-butyloxycarbonyl)guanidinomethyl-3-trimethylsilylbenzoic acid proceeded in less than 5% radiochemical yield. A more successful approachwas to prepare [¹³¹I]SGMIB directly from the tin precursor, N-succinimidyl 4-(N¹,N²-bis-tert-butyloxycarbonyl)guanidinomethyl-3-trimethylstannylbenzoate, which was achieved in 60-65% radiochemical yield. A rapidly internalizing anti-epidermal growth factor receptor variant III antibodyL8A4 was labeled using [¹³¹I]SGMIB in 65% conjugation efficiency and with preservation ofimmunoreactivity. Paired-label in vitro internalization assays demonstrated that the amount ofradioactivity retained in cells after internalization for L8A4 labeled with [¹³¹I]SGMIB was 3-4-foldhigher than that for L8A4 labeled with ¹²⁵I using either Iodogen or [¹²⁵I]SIPC. Catabolite assaysdocumented that the increased retention of radioiodine in tumor cells for antibody labeled using [¹³¹I]SGMIB was due to positively charged, low molecular weight species. These results suggest that [¹³¹I]SGMIB warrants further evaluation as a reagent for labeling internalizing antibodies.