PMID- 8868284
OWN - NLM
STAT- MEDLINE
DCOM- 19970130
LR  - 20190920
IS  - 0969-8051 (Print)
IS  - 0969-8051 (Linking)
VI  - 23
IP  - 2
DP  - 1996 Feb
TI  - Stability of a metabolizable ester bond in radioimmunoconjugates.
PG  - 129-36
AB  - Ester bonds have been used as metabolizable linkages to reduce radioactivity 
      levels in non-target tissues following the administration of antibodies labeled 
      with metallic radionuclides. In this radiochemical 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, IgG1) 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-[131I]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-111In 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-131I 
      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-131I 
      than with OST7-EMCS-Bz-EDTA-111In, OST7-MESS-Bz-EDTA-111In indicated 
      radioactivity clearance from the blood much faster than and almost comparable to 
      that of OST7-MIH-131I and succinamidobenzyl-EDTA-111In, 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.
FAU - Arano, Y
AU  - Arano Y
AD  - Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
FAU - Wakisaka, K
AU  - Wakisaka K
FAU - Mukai, T
AU  - Mukai T
FAU - Uezono, T
AU  - Uezono T
FAU - Motonari, H
AU  - Motonari H
FAU - Akizawa, H
AU  - Akizawa H
FAU - Kairiyama, C
AU  - Kairiyama C
FAU - Ohmomo, Y
AU  - Ohmomo Y
FAU - Tanaka, C
AU  - Tanaka C
FAU - Ishiyama, M
AU  - Ishiyama M
FAU - Sakahara, H
AU  - Sakahara H
FAU - Konishi, J
AU  - Konishi J
FAU - Yokoyama, A
AU  - Yokoyama A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Nucl Med Biol
JT  - Nuclear medicine and biology
JID - 9304420
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Esters)
RN  - 0 (Immunoconjugates)
RN  - 0 (Indium Radioisotopes)
RN  - 0 
      (OST7-(1-(4-(4-(2-maleimidoethoxy)succinamido)benzyl)ethylenediamine-N,N,N',N'-tetraacetic 
      acid))
RN  - 9G34HU7RV0 (Edetic Acid)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/*chemistry/pharmacokinetics
MH  - Chromatography, Gel
MH  - Chromatography, Thin Layer
MH  - Edetic Acid/*analogs & derivatives/chemistry/pharmacokinetics
MH  - Esters/chemistry/metabolism
MH  - Immunoconjugates/*chemistry/metabolism/pharmacokinetics
MH  - Indium Radioisotopes
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Rats
MH  - Tissue Distribution
EDAT- 1996/02/01 00:00
MHDA- 1996/02/01 00:01
CRDT- 1996/02/01 00:00
PHST- 1996/02/01 00:00 [pubmed]
PHST- 1996/02/01 00:01 [medline]
PHST- 1996/02/01 00:00 [entrez]
AID - 0969-8051(95)02042-X [pii]
AID - 10.1016/0969-8051(95)02042-x [doi]
PST - ppublish
SO  - Nucl Med Biol. 1996 Feb;23(2):129-36. doi: 10.1016/0969-8051(95)02042-x.