Stability of a metabolizable ester bond in radioimmunoconjugates

被引:20
作者
Arano, Y
Wakisaka, K
Mukai, T
Uezono, T
Motonari, H
Akizawa, H
Kairiyama, C
Ohmomo, Y
Tanaka, C
Ishiyama, M
Sakahara, H
Konishi, J
Yokoyama, A
机构
[1] KYOTO UNIV, FAC PHARMACEUT SCI, DEPT RADIOPHARMACEUT CHEM, SAKYO KU, KYOTO 60601, JAPAN
[2] KYOTO UNIV, FAC MED, SAKYO KU, KYOTO 60601, JAPAN
[3] OSAKA UNIV PHARMACEUT SCI, MATSUBARA, OSAKA 567, JAPAN
[4] DOJINDO LAB, KUMAMOTO 86122, JAPAN
关键词
monoclonal antibody; targeting; conjugate; ester bond; radioimmunoimaging; radioimmunotherapy;
D O I
10.1016/0969-8051(95)02042-X
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
Ester bonds have been used as metabolizable linkages to reduce radioactivity levels in nontarget tissues following the administration of antibodies labeled with metallic radionuclides, In this radio chemical design of antibodies, while the ester bonds should be cleaved rapidly in non target tissues, high stability of the ester bonds in plasma is also required to preserve target radioactivity levels. To assess the structural requirements to stabilize the ester bond, a new benzyl-EDTA-derived bifunctional chelating agent with an ester bond, (1-[4-[4-(2-maleimidoethoxy)succinamido]benzyl]ethylenediamine N,N,N',N'-tetraacetic acid; MESS-Bz-EDTA), was developed, MESS-Bz-EDTA was coupled with a thiolated monoclonal antibody (OST7, IgG(1)) prepared by reducing its disulfide bonds to introduce the ester bond close and proximal to the antibody molecule. For comparison, 1-[4-(5-maleimidopentyl)aminobenzyl]ethylenediamine-N, N,N',N'-tetraacetic acid (EMCS-Bz-EDTA) and meleimidoethyl 3-[I-131]iodohippurate (MIH) was coupled to OST7 under the same conjunction chemistry. When incubated in 50% murine plasma or a buffered solution of neutral pH, OST7-MESS-Bz-EDTA-In-111 rapidly released the radioactivity, and more than 95% of the initial radioactivity was liberated after a 24 h incubation in both solutions, due to a cleavage of the ester bond. On the other hand, only about 20% of the radioactivity was released from OST7-MIH-I-131 in both solutions during the same incubation period. In mice biodistribution studies, while a slightly faster radioactivity clearance from the blood with less radioactivity levels in the liver and kidneys was observed with OST7-MIH-I-131 than with OST7-EMCS-Bz-EDTA-In-111, OST7-MESS-Bz-EDTA-In-111 indicated radioactivity clearance from the blood much faster than and almost comparable to that of OST7-MIH-I-131 and succinamidobenzyl-EDTA-In-111, respectively. These findings as well as previous findings on radiolabeled antibodies with ester bonds suggested that while an introduction of an ester bond close to an antibody molecule stabilized the ester bond against esterase access, chemical structures of the linkages and radiolabels attached to the ester bonds play a significant role in the chemical stability of the ester bond, This may explain the different stability of the ester bonds in radioimmunoconjugates so far reported.
引用
收藏
页码:129 / 136
页数:8
相关论文
共 27 条
[1]  
ALBERTS B, 1983, MOL BIOL CELL, P302
[2]  
ARANO Y, 1986, APPL RADIAT ISOTOPES, V37, P587
[3]   A NOVEL BIFUNCTIONAL METABOLIZABLE LINKER FOR THE CONJUGATION OF ANTIBODIES WITH RADIONUCLIDES [J].
ARANO, Y ;
MATSUSHIMA, H ;
TAGAWA, M ;
KOIZUMI, M ;
ENDO, K ;
KONISHI, J ;
YOKOYAMA, A .
BIOCONJUGATE CHEMISTRY, 1991, 2 (02) :71-76
[4]   RADIOLABELED METABOLITES OF PROTEINS PLAY A CRITICAL ROLE IN RADIOACTIVITY ELIMINATION FROM THE LIVER [J].
ARANO, Y ;
MUKAI, T ;
AKIZAWA, H ;
UEZONO, T ;
MOTONARI, H ;
WAKISAKA, K ;
KAIRIYAMA, C ;
YOKOYAMA, A .
NUCLEAR MEDICINE AND BIOLOGY, 1995, 22 (05) :555-564
[5]   MALEIMIDOETHYL 3-(TRI-N-BUTYLSTANNYL)HIPPURATE - A USEFUL RADIOIODINATION REAGENT FOR PROTEIN RADIOPHARMACEUTICALS TO ENHANCE TARGET SELECTIVE RADIOACTIVITY LOCALIZATION [J].
ARANO, Y ;
WAKISAKA, K ;
OHMOMO, Y ;
UEZONO, T ;
MUKAI, T ;
MOTONARI, H ;
SHIONO, H ;
SAKAHARA, H ;
KONISHI, J ;
TANAKA, C ;
YOKOYAMA, A .
JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (16) :2609-2618
[6]  
ARANO Y, 1994, J NUCL MED, V35, P890
[7]  
ARANO Y, 1994, J NUCL MED, V35, P326
[8]   RADIOLABELED BENZOYLCHOLINE DERIVATIVES AS POSSIBLE MYOCARDIAL-IMAGING AGENTS [J].
DANNALS, RF ;
BURNS, HD ;
MARZILLI, LG ;
TRAGESER, TC ;
WAGNER, HN .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1981, 70 (04) :439-442
[9]  
DORRINGTON KJ, 1972, ADV IMMUNOL, V12, P333
[10]  
DUNCAN JR, 1993, J NUCL MED, V34, P1728