Assessment of Radiochemical Design of Antibodies Using an Ester Bond as the Metabolizable Linkage: Evaluation of Maleimidoethyl 3-(Tri-n-butylstannyl)hippurate as a Radioiodination Reagent of A

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• 作者：Yasushi Arano ; Kouji Wakisaka ; Yoshiro Ohmono ; Takashi Uezono ; Hiromichi Akizawa ; Morio Nakayama ; Harumi Sakahara ; Chiaki Tanaka ; Junji Konishi ; and Akira Yokoyama
• 刊名：Bioconjugate Chemistry
• 出版年：1996
• 出版时间：November 1996
• 年：1996
• 卷：7
• 期：6
• 页码：628 - 637
• 全文大小：426K
• 年卷期：v.7,no.6(November 1996)
• ISSN：1520-4812

文摘

Reduction of radioactivity levels in nontarget tissues such as the liverand kidney constitutes a problemto be resolved in diagnostic and therapeutic applications ofradiolabeled monoclonal antibodies (mAbs).A new radioiodination reagent with an ester bond to liberatem-iodohippuric acid from covalentlyconjugated proteins, maleimidoethyl3-(tri-n-butylstannyl)hippurate (MIH), was recentlydeveloped.MIH liberated m-iodohippuric acid fromgalactosylneoglycoalbumin in murine liver, and the radiometabolite was rapidly eliminated from the liver into urine as anintact structure. In this study,intact IgG and Fab fragment of a mAb against osteogenic sarcoma wereradioiodinated with MIH tofurther assess the applicability of MIH to radioimmunoimaging andtherapy. For comparison, a mAbradioiodinated with N-succinimidyl iodobenzoate (SIB) andindium-111 (¹¹¹In)-labeled mAbs withdiethylenetriaminepentaacetic dianhydride (cDTPA) or1-[4-[(5-maleimidopentyl)amino]benzyl]ethylenediaminetetraacetic acid (EMCS-Bz-EDTA) were used.Size-exclusion HPLC analysis and cellbinding assays indicated the preservation of both structure and antigenbinding affinity of radioiodinated MIH-OST7 (IgG). In biodistribution studies in mice,[¹²⁵I]MIH-OST7 (IgG) showed fastersystemic clearance of radioactivity after 24 h postinjection than did[¹³¹I]SIB- and[¹¹¹In]EMCS-Bz-EDTA-OST7 (IgG). [¹²⁵I]MIH-OST7 (IgG) alsoexhibited much lower radioactivity levels in nontargettissues such as the liver and kidney, with higher radioactivity levelsin the blood up to 72 h postinjectionwhen compared with [¹¹¹In]cDTPA-OST7 (IgG).Radioactivity excreted from the mice was found inthe urine as m-iodohippuric acid, following administrationof [¹²⁵I]MIH-OST7 (IgG). In athymicmicebearing osteogenic sarcoma, [¹³¹I]MIH-OST7 (IgG)indicated higher tumor-to-nontarget ratios ofradioactivity at both 24 and 48 h postinjection than[¹²⁵I]SIB-OST7 (IgG). Although bothradioiodinated OST7s showed similar radioactivity levels in the target at 24 hpostinjection, a small butsignificant decrease in the target radioactivity level was observedwith [¹³¹I]MIH-OST7 (IgG) at 48h postinjection. In addition, [¹³¹I]MIH-OST7(Fab) showed very rapid cleavage of the ester bondboth in vivo and in vitro. These findingsindicated that while MIH may be a useful reagent forradioimmunoimaging using IgG mAb, its application to smaller molecularweight mAbs andradioimmunotherapy would be hindered due to the labile characteristicsof the ester bond in plasma.Thus, while the present study reinforced the usefulness ofmetabolizable linkages for reducingnontarget radioactivity levels, a development of plasma-stablemetabolizable linkages is also warrantedfor radioimmunotherapy and for smaller molecular weightpolypeptides.