The Experts below are selected from a list of 16101 Experts worldwide ranked by ideXlab platform

Akira Yokoyama - One of the best experts on this subject based on the ideXlab platform.

  • 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 antibodies for diagnostic and therapeutic applications.
    Bioconjugate chemistry, 1996
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takashi Uezono, Hiromichi Akizawa, Chiaki Tanaka, Yoshiro Ohmono, Morio Nakayama, Harumi Sakahara, Junji Konishi, Akira Yokoyama
    Abstract:

    Reduction of radioactivity levels in nontarget tissues such as the liver and kidney constitutes a problem to be resolved in diagnostic and therapeutic applications of radiolabeled monoclonal antibodies (mAbs). A new radioiodination reagent with an Ester Bond to liberate m-iodohippuric acid from covalently conjugated proteins, maleimidoethyl 3-(tri-n-butylstannyl)hippurate (MIH), was recently developed. MIH liberated m-iodohippuric acid from galactosylneoglycoalbumin in murine liver, and the radiometabolite was rapidly eliminated from the liver into urine as an intact structure. In this study, intact IgG and Fab fragment of a mAb against osteogenic sarcoma were radioiodinated with MIH to further assess the applicability of MIH to radioimmunoimaging and therapy. For comparison, a mAb radioiodinated with N-succinimidyl iodobenzoate (SIB) and indium-111 (111In)-labeled mAbs with diethylenetriaminepentaacetic dianhydride (cDTPA) or 1-[4-[(5-maleimidopentyl)amino]benzyl]-ethylenediaminetetraacetic acid (EMCS-Bz-EDTA) were used. Size-exclusion HPLC analysis and cell binding assays indicated the preservation of both structure and antigen binding affinity of radioiodinated MIH-OST7 (IgG). In biodistribution studies in mice, [125I]MIH-OST7 (IgG) showed faster systemic clearance of radioactivity after 24 h postinjection than did [131I]SIB- and [111In]EMCS-Bz-EDTA-OST7 (IgG). [125I]MIH-OST7 (IgG) also exhibited much lower radioactivity levels in nontarget tissues such as the liver and kidney, with higher radioactivity levels in the blood up to 72 h postinjection when compared with [111In]cDTPA-OST7 (IgG). Radioactivity excreted from the mice was found in the urine as m-iodohippuric acid, following administration of [125I]MIH-OST7 (IgG). In athymic mice bearing osteogenic sarcoma, [131I]MIH-OST7 (IgG) indicated higher tumor-to-nontarget ratios of radioactivity at both 24 and 48 h postinjection than [125I]SIB-OST7 (IgG). Although both radioiodinated OST7s showed similar radioactivity levels in the target at 24 h postinjection, a small but significant decrease in the target radioactivity level was observed with [131I]MIH-OST7 (IgG) at 48 h postinjection. In addition, [131I]MIH-OST7 (Fab) showed very rapid cleavage of the Ester Bond both in vivo and in vitro. These findings indicated that while MIH may be a useful reagent for radioimmunoimaging using IgG, mAb, its application to smaller molecular weight mAbs and radioimmunotherapy would be hindered due to the labile characteristics of the Ester Bond in plasma. Thus, while the present study reinforced the usefulness of metabolizable linkages for reducing nontarget radioactivity levels, a development of plasma-stable metabolizable linkages is also warranted for radioimmunotherapy and for smaller molecular weight polypeptides.

  • 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 antibodies for diagnostic and therapeutic applications
    Bioconjugate Chemistry, 1996
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takashi Uezono, Hiromichi Akizawa, Chiaki Tanaka, Yoshiro Ohmono, Morio Nakayama, Harumi Sakahara, Junji Konishi, Akira Yokoyama
    Abstract:

    Reduction of radioactivity levels in nontarget tissues such as the liver and kidney constitutes a problem to be resolved in diagnostic and therapeutic applications of radiolabeled monoclonal antibodies (mAbs). A new radioiodination reagent with an Ester Bond to liberate m-iodohippuric acid from covalently conjugated proteins, maleimidoethyl 3-(tri-n-butylstannyl)hippurate (MIH), was recently developed. MIH liberated m-iodohippuric acid from galactosylneoglycoalbumin in murine liver, and the radiometabolite was rapidly eliminated from the liver into urine as an intact structure. In this study, intact IgG and Fab fragment of a mAb against osteogenic sarcoma were radioiodinated with MIH to further assess the applicability of MIH to radioimmunoimaging and therapy. For comparison, a mAb radioiodinated with N-succinimidyl iodobenzoate (SIB) and indium-111 (111In)-labeled mAbs with diethylenetriaminepentaacetic dianhydride (cDTPA) or 1-[4-[(5-maleimidopentyl)amino]benzyl]ethylenediaminetetraacetic acid (EMCS-Bz-...

  • discriminated release of a hippurate like radiometal chelate in nontarget tissues for target selective radioactivity localization using ph dependent dissociation of reduced antibody
    The Journal of Nuclear Medicine, 1994
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takahiro Mukai, Harumi Sakahara, Junji Konishi, Tatsuo Inoue, Akira Yokoyama
    Abstract:

    UNLABELLED: To achieve high and selective target radioactivity localization by monoclonal antibodies (Mabs) labeled with metallic radionuclides, the discriminated release of a hippurate-like radiometal chelate in nontarget tissues was performed using chemically modified Mabs. METHODS: The disulfide Bonds of a Mab against osteogenic sarcoma (OST7, IgG1) were reduced and 67Ga chelate of succinyldeferoxamine (SDF) was conjugated proximal to the Mab molecule via an Ester Bond with exposed thiol groups (67Ga-DFO-MESS-redOST7), which would impair Esterase access to the Ester Bond of 67Ga-DFO-MESS-redOST7 due to the steric interference induced by bulky antibody molecule, stabilizing the Ester Bond in plasma and on the target cell's surface. Gallium-67-SDF was also conjugated to OST7 via an Ester Bond with 2-iminothiolane to render the Ester Bond in a position distal from the OST7 molecule (67Ga-DFO-MESS-IT-OST7). RESULTS: Although SDS-PAGE analyses of 67Ga-DFO-MESS-redOST7 showed a partial cleavage of its disulfide Bonds, size-exclusion HPLC and cell binding assays indicated that the IgG structure and immunoreactivity of this conjugate were preserved in a neutral buffer and plasma of the systemic circulation. CONCLUSION: The present radiochemical design of an antibody utilizing pH-dependent dissociation would constitute a promising approach in establishing selective target radioactivity localization by Mabs.

  • discriminated release of a hippurate like radiometal chelate in nontarget tissues for target selective radioactivity localization using ph dependent dissociation of reduced antibody
    The Journal of Nuclear Medicine, 1994
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takahiro Mukai, Harumi Sakahara, Junji Konishi, Tatsuo Inoue, Akira Yokoyama
    Abstract:

    To achieve high and selective target radioactivity localization by monoclonal antibodies (Mabs) labeled with metallic radionuclides, the discriminated release of a hippurate-like radiometal chelate in nontarget tissues was performed using chemically modified Mabs. Methods: The disulfide Bonds of a Mab against osteogenic sarcoma (OST7, IgG 1 ) were reduced and 67 Ga chelate of succinyldeferoxamine (SDF) was conjugated proximal to the Mab molecule via an Ester Bond with exposed thiol groups ( 67 Ga-DFO-MESS-redOST7), which would impair Esterase access to the Ester Bond of 67 Ga-DFO-MESS-redOST7 due to the steric interference induced by bulky antibody molecule, stabilizing the Ester Bond in plasma and on the target cell's surface

Yasushi Arano - One of the best experts on this subject based on the ideXlab platform.

  • Stability of a metabolizable Ester Bond in radioimmunoconjugates
    Nuclear Medicine and Biology, 1996
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takahiro Mukai, Takashi Uezono, Hiroshi Motonari, Hiromichi Akizawa, Claudia Kairiyama, Yoshiro Ohmomo, Chiaki Tanaka, Munetaka Ishiyama
    Abstract:

    Abstract 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, 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-[ 131 I]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- 111 In 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- 131 I 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- 131 I than with OST7-EMCS-Bz-EDTA- 111 In, OST7-MESS-Bz-EDTA- 111 In indicated radioactivity clearance from the blood much faster than and almost comparable to that of OST7-MIH- 131 I and succinamidobenzyl-EDTA- 111 In, 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.

  • 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 antibodies for diagnostic and therapeutic applications.
    Bioconjugate chemistry, 1996
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takashi Uezono, Hiromichi Akizawa, Chiaki Tanaka, Yoshiro Ohmono, Morio Nakayama, Harumi Sakahara, Junji Konishi, Akira Yokoyama
    Abstract:

    Reduction of radioactivity levels in nontarget tissues such as the liver and kidney constitutes a problem to be resolved in diagnostic and therapeutic applications of radiolabeled monoclonal antibodies (mAbs). A new radioiodination reagent with an Ester Bond to liberate m-iodohippuric acid from covalently conjugated proteins, maleimidoethyl 3-(tri-n-butylstannyl)hippurate (MIH), was recently developed. MIH liberated m-iodohippuric acid from galactosylneoglycoalbumin in murine liver, and the radiometabolite was rapidly eliminated from the liver into urine as an intact structure. In this study, intact IgG and Fab fragment of a mAb against osteogenic sarcoma were radioiodinated with MIH to further assess the applicability of MIH to radioimmunoimaging and therapy. For comparison, a mAb radioiodinated with N-succinimidyl iodobenzoate (SIB) and indium-111 (111In)-labeled mAbs with diethylenetriaminepentaacetic dianhydride (cDTPA) or 1-[4-[(5-maleimidopentyl)amino]benzyl]-ethylenediaminetetraacetic acid (EMCS-Bz-EDTA) were used. Size-exclusion HPLC analysis and cell binding assays indicated the preservation of both structure and antigen binding affinity of radioiodinated MIH-OST7 (IgG). In biodistribution studies in mice, [125I]MIH-OST7 (IgG) showed faster systemic clearance of radioactivity after 24 h postinjection than did [131I]SIB- and [111In]EMCS-Bz-EDTA-OST7 (IgG). [125I]MIH-OST7 (IgG) also exhibited much lower radioactivity levels in nontarget tissues such as the liver and kidney, with higher radioactivity levels in the blood up to 72 h postinjection when compared with [111In]cDTPA-OST7 (IgG). Radioactivity excreted from the mice was found in the urine as m-iodohippuric acid, following administration of [125I]MIH-OST7 (IgG). In athymic mice bearing osteogenic sarcoma, [131I]MIH-OST7 (IgG) indicated higher tumor-to-nontarget ratios of radioactivity at both 24 and 48 h postinjection than [125I]SIB-OST7 (IgG). Although both radioiodinated OST7s showed similar radioactivity levels in the target at 24 h postinjection, a small but significant decrease in the target radioactivity level was observed with [131I]MIH-OST7 (IgG) at 48 h postinjection. In addition, [131I]MIH-OST7 (Fab) showed very rapid cleavage of the Ester Bond both in vivo and in vitro. These findings indicated that while MIH may be a useful reagent for radioimmunoimaging using IgG, mAb, its application to smaller molecular weight mAbs and radioimmunotherapy would be hindered due to the labile characteristics of the Ester Bond in plasma. Thus, while the present study reinforced the usefulness of metabolizable linkages for reducing nontarget radioactivity levels, a development of plasma-stable metabolizable linkages is also warranted for radioimmunotherapy and for smaller molecular weight polypeptides.

  • 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 antibodies for diagnostic and therapeutic applications
    Bioconjugate Chemistry, 1996
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takashi Uezono, Hiromichi Akizawa, Chiaki Tanaka, Yoshiro Ohmono, Morio Nakayama, Harumi Sakahara, Junji Konishi, Akira Yokoyama
    Abstract:

    Reduction of radioactivity levels in nontarget tissues such as the liver and kidney constitutes a problem to be resolved in diagnostic and therapeutic applications of radiolabeled monoclonal antibodies (mAbs). A new radioiodination reagent with an Ester Bond to liberate m-iodohippuric acid from covalently conjugated proteins, maleimidoethyl 3-(tri-n-butylstannyl)hippurate (MIH), was recently developed. MIH liberated m-iodohippuric acid from galactosylneoglycoalbumin in murine liver, and the radiometabolite was rapidly eliminated from the liver into urine as an intact structure. In this study, intact IgG and Fab fragment of a mAb against osteogenic sarcoma were radioiodinated with MIH to further assess the applicability of MIH to radioimmunoimaging and therapy. For comparison, a mAb radioiodinated with N-succinimidyl iodobenzoate (SIB) and indium-111 (111In)-labeled mAbs with diethylenetriaminepentaacetic dianhydride (cDTPA) or 1-[4-[(5-maleimidopentyl)amino]benzyl]ethylenediaminetetraacetic acid (EMCS-Bz-...

  • discriminated release of a hippurate like radiometal chelate in nontarget tissues for target selective radioactivity localization using ph dependent dissociation of reduced antibody
    The Journal of Nuclear Medicine, 1994
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takahiro Mukai, Harumi Sakahara, Junji Konishi, Tatsuo Inoue, Akira Yokoyama
    Abstract:

    UNLABELLED: To achieve high and selective target radioactivity localization by monoclonal antibodies (Mabs) labeled with metallic radionuclides, the discriminated release of a hippurate-like radiometal chelate in nontarget tissues was performed using chemically modified Mabs. METHODS: The disulfide Bonds of a Mab against osteogenic sarcoma (OST7, IgG1) were reduced and 67Ga chelate of succinyldeferoxamine (SDF) was conjugated proximal to the Mab molecule via an Ester Bond with exposed thiol groups (67Ga-DFO-MESS-redOST7), which would impair Esterase access to the Ester Bond of 67Ga-DFO-MESS-redOST7 due to the steric interference induced by bulky antibody molecule, stabilizing the Ester Bond in plasma and on the target cell's surface. Gallium-67-SDF was also conjugated to OST7 via an Ester Bond with 2-iminothiolane to render the Ester Bond in a position distal from the OST7 molecule (67Ga-DFO-MESS-IT-OST7). RESULTS: Although SDS-PAGE analyses of 67Ga-DFO-MESS-redOST7 showed a partial cleavage of its disulfide Bonds, size-exclusion HPLC and cell binding assays indicated that the IgG structure and immunoreactivity of this conjugate were preserved in a neutral buffer and plasma of the systemic circulation. CONCLUSION: The present radiochemical design of an antibody utilizing pH-dependent dissociation would constitute a promising approach in establishing selective target radioactivity localization by Mabs.

  • discriminated release of a hippurate like radiometal chelate in nontarget tissues for target selective radioactivity localization using ph dependent dissociation of reduced antibody
    The Journal of Nuclear Medicine, 1994
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takahiro Mukai, Harumi Sakahara, Junji Konishi, Tatsuo Inoue, Akira Yokoyama
    Abstract:

    To achieve high and selective target radioactivity localization by monoclonal antibodies (Mabs) labeled with metallic radionuclides, the discriminated release of a hippurate-like radiometal chelate in nontarget tissues was performed using chemically modified Mabs. Methods: The disulfide Bonds of a Mab against osteogenic sarcoma (OST7, IgG 1 ) were reduced and 67 Ga chelate of succinyldeferoxamine (SDF) was conjugated proximal to the Mab molecule via an Ester Bond with exposed thiol groups ( 67 Ga-DFO-MESS-redOST7), which would impair Esterase access to the Ester Bond of 67 Ga-DFO-MESS-redOST7 due to the steric interference induced by bulky antibody molecule, stabilizing the Ester Bond in plasma and on the target cell's surface

Q. Ping Dou - One of the best experts on this subject based on the ideXlab platform.

  • Direct inhibition of the ubiquitin-proteasome pathway by Ester Bond-containing green tea polyphenols is associated with increased expression of sterol regulatory element-binding protein 2 and LDL receptor.
    Biochimica et Biophysica Acta, 2004
    Co-Authors: Deborah J. Kuhn, Audrey C Burns, Aslamuzzaman Kazi, Q. Ping Dou
    Abstract:

    Green tea has been shown to lower plasma cholEsterol, associated with up-regulation of the low-density lipoprotein receptor (LDLR) although the responsible molecular mechanism is unknown. Previously, we reported that Ester Bond-containing green tea polyphenols (GTPs), such as (-)-epigallocatechin-3-gallate [(-)-EGCG], potently inhibit the tumor cellular proteasome activity, which may contribute to the cancer-preventative effect of green tea. In the current study, we hypothesize that the proteasome is a heart disease-associated molecular target of GTPs. We have shown that Ester Bond-containing GTPs, including (-)-EGCG, potently inhibit the proteasomal activity in intact hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cells, as evident by accumulation of ubiquitinated proteins and three natural proteasome targets (p27, IkappaB-alpha and Bax). (-)-EGCG selectively inhibits the chymotrypsin-like, but not trypsin-like, activity of the proteasome. Associated with proteasome inhibition by Ester Bond-containing GTPs, there was a significant, time- and concentration-dependent increase in levels of the cleaved, activated, but not the precursor, form of sterol regulatory element-binding protein 2 (SREBP-2), an essential factor for LDLR transcription. Subsequently, LDL receptor expression was increased dramatically in HepG2 and HeLa cells treated with (-)-EGCG. Our results suggest that Ester Bond-containing GTPs inhibit ubiquitin/proteasome-mediated degradation of the active SREBP-2, resulting in up-regulation of LDLR. This identified molecular mechanism may be related to the previously reported cholEsterol-lowering and heart disease-preventative effects of green tea.

  • Ester Bond-containing Tea Polyphenols Potently Inhibit Proteasome Activity in Vitro and in Vivo
    The Journal of biological chemistry, 2001
    Co-Authors: Sangkil Nam, David M. Smith, Q. Ping Dou
    Abstract:

    Abstract It has been discovered that proteasome inhibitors are able to induce tumor growth arrest or cell death and that tea consumption is correlated with cancer prevention. Here, we show that Ester Bond-containing tea polyphenols, such as (−)−epigallocatechin-3-gallate (EGCG), potently and specifically inhibit the chymotrypsin-like activity of the proteasome in vitro (IC50 = 86–194 nm) and in vivo (1–10 μm) at the concentrations found in the serum of green tea drinkers. Atomic orbital energy analyses and high performance liquid chromatography suggest that the carbon of the polyphenol Ester Bond is essential for targeting, thereby inhibiting the proteasome in cancer cells. This inhibition of the proteasome by EGCG in several tumor and transformed cell lines results in the accumulation of two natural proteasome substrates, p27Kip1and IκB-α, an inhibitor of transcription factor NF-κB, followed by growth arrest in the G1 phase of the cell cycle. Furthermore, compared with their simian virus-transformed counterpart, the parental normal human fibroblasts were much more resistant to EGCG-induced p27Kip1 protein accumulation and G1 arrest. Our study suggests that the proteasome is a cancer-related molecular target of tea polyphenols and that inhibition of the proteasome activity by Ester Bond-containing polyphenols may contribute to the cancer-preventative effect of tea.

Kouji Wakisaka - One of the best experts on this subject based on the ideXlab platform.

  • Stability of a metabolizable Ester Bond in radioimmunoconjugates
    Nuclear Medicine and Biology, 1996
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takahiro Mukai, Takashi Uezono, Hiroshi Motonari, Hiromichi Akizawa, Claudia Kairiyama, Yoshiro Ohmomo, Chiaki Tanaka, Munetaka Ishiyama
    Abstract:

    Abstract 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, 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-[ 131 I]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- 111 In 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- 131 I 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- 131 I than with OST7-EMCS-Bz-EDTA- 111 In, OST7-MESS-Bz-EDTA- 111 In indicated radioactivity clearance from the blood much faster than and almost comparable to that of OST7-MIH- 131 I and succinamidobenzyl-EDTA- 111 In, 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.

  • 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 antibodies for diagnostic and therapeutic applications.
    Bioconjugate chemistry, 1996
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takashi Uezono, Hiromichi Akizawa, Chiaki Tanaka, Yoshiro Ohmono, Morio Nakayama, Harumi Sakahara, Junji Konishi, Akira Yokoyama
    Abstract:

    Reduction of radioactivity levels in nontarget tissues such as the liver and kidney constitutes a problem to be resolved in diagnostic and therapeutic applications of radiolabeled monoclonal antibodies (mAbs). A new radioiodination reagent with an Ester Bond to liberate m-iodohippuric acid from covalently conjugated proteins, maleimidoethyl 3-(tri-n-butylstannyl)hippurate (MIH), was recently developed. MIH liberated m-iodohippuric acid from galactosylneoglycoalbumin in murine liver, and the radiometabolite was rapidly eliminated from the liver into urine as an intact structure. In this study, intact IgG and Fab fragment of a mAb against osteogenic sarcoma were radioiodinated with MIH to further assess the applicability of MIH to radioimmunoimaging and therapy. For comparison, a mAb radioiodinated with N-succinimidyl iodobenzoate (SIB) and indium-111 (111In)-labeled mAbs with diethylenetriaminepentaacetic dianhydride (cDTPA) or 1-[4-[(5-maleimidopentyl)amino]benzyl]-ethylenediaminetetraacetic acid (EMCS-Bz-EDTA) were used. Size-exclusion HPLC analysis and cell binding assays indicated the preservation of both structure and antigen binding affinity of radioiodinated MIH-OST7 (IgG). In biodistribution studies in mice, [125I]MIH-OST7 (IgG) showed faster systemic clearance of radioactivity after 24 h postinjection than did [131I]SIB- and [111In]EMCS-Bz-EDTA-OST7 (IgG). [125I]MIH-OST7 (IgG) also exhibited much lower radioactivity levels in nontarget tissues such as the liver and kidney, with higher radioactivity levels in the blood up to 72 h postinjection when compared with [111In]cDTPA-OST7 (IgG). Radioactivity excreted from the mice was found in the urine as m-iodohippuric acid, following administration of [125I]MIH-OST7 (IgG). In athymic mice bearing osteogenic sarcoma, [131I]MIH-OST7 (IgG) indicated higher tumor-to-nontarget ratios of radioactivity at both 24 and 48 h postinjection than [125I]SIB-OST7 (IgG). Although both radioiodinated OST7s showed similar radioactivity levels in the target at 24 h postinjection, a small but significant decrease in the target radioactivity level was observed with [131I]MIH-OST7 (IgG) at 48 h postinjection. In addition, [131I]MIH-OST7 (Fab) showed very rapid cleavage of the Ester Bond both in vivo and in vitro. These findings indicated that while MIH may be a useful reagent for radioimmunoimaging using IgG, mAb, its application to smaller molecular weight mAbs and radioimmunotherapy would be hindered due to the labile characteristics of the Ester Bond in plasma. Thus, while the present study reinforced the usefulness of metabolizable linkages for reducing nontarget radioactivity levels, a development of plasma-stable metabolizable linkages is also warranted for radioimmunotherapy and for smaller molecular weight polypeptides.

  • 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 antibodies for diagnostic and therapeutic applications
    Bioconjugate Chemistry, 1996
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takashi Uezono, Hiromichi Akizawa, Chiaki Tanaka, Yoshiro Ohmono, Morio Nakayama, Harumi Sakahara, Junji Konishi, Akira Yokoyama
    Abstract:

    Reduction of radioactivity levels in nontarget tissues such as the liver and kidney constitutes a problem to be resolved in diagnostic and therapeutic applications of radiolabeled monoclonal antibodies (mAbs). A new radioiodination reagent with an Ester Bond to liberate m-iodohippuric acid from covalently conjugated proteins, maleimidoethyl 3-(tri-n-butylstannyl)hippurate (MIH), was recently developed. MIH liberated m-iodohippuric acid from galactosylneoglycoalbumin in murine liver, and the radiometabolite was rapidly eliminated from the liver into urine as an intact structure. In this study, intact IgG and Fab fragment of a mAb against osteogenic sarcoma were radioiodinated with MIH to further assess the applicability of MIH to radioimmunoimaging and therapy. For comparison, a mAb radioiodinated with N-succinimidyl iodobenzoate (SIB) and indium-111 (111In)-labeled mAbs with diethylenetriaminepentaacetic dianhydride (cDTPA) or 1-[4-[(5-maleimidopentyl)amino]benzyl]ethylenediaminetetraacetic acid (EMCS-Bz-...

  • discriminated release of a hippurate like radiometal chelate in nontarget tissues for target selective radioactivity localization using ph dependent dissociation of reduced antibody
    The Journal of Nuclear Medicine, 1994
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takahiro Mukai, Harumi Sakahara, Junji Konishi, Tatsuo Inoue, Akira Yokoyama
    Abstract:

    UNLABELLED: To achieve high and selective target radioactivity localization by monoclonal antibodies (Mabs) labeled with metallic radionuclides, the discriminated release of a hippurate-like radiometal chelate in nontarget tissues was performed using chemically modified Mabs. METHODS: The disulfide Bonds of a Mab against osteogenic sarcoma (OST7, IgG1) were reduced and 67Ga chelate of succinyldeferoxamine (SDF) was conjugated proximal to the Mab molecule via an Ester Bond with exposed thiol groups (67Ga-DFO-MESS-redOST7), which would impair Esterase access to the Ester Bond of 67Ga-DFO-MESS-redOST7 due to the steric interference induced by bulky antibody molecule, stabilizing the Ester Bond in plasma and on the target cell's surface. Gallium-67-SDF was also conjugated to OST7 via an Ester Bond with 2-iminothiolane to render the Ester Bond in a position distal from the OST7 molecule (67Ga-DFO-MESS-IT-OST7). RESULTS: Although SDS-PAGE analyses of 67Ga-DFO-MESS-redOST7 showed a partial cleavage of its disulfide Bonds, size-exclusion HPLC and cell binding assays indicated that the IgG structure and immunoreactivity of this conjugate were preserved in a neutral buffer and plasma of the systemic circulation. CONCLUSION: The present radiochemical design of an antibody utilizing pH-dependent dissociation would constitute a promising approach in establishing selective target radioactivity localization by Mabs.

  • discriminated release of a hippurate like radiometal chelate in nontarget tissues for target selective radioactivity localization using ph dependent dissociation of reduced antibody
    The Journal of Nuclear Medicine, 1994
    Co-Authors: Yasushi Arano, Kouji Wakisaka, Takahiro Mukai, Harumi Sakahara, Junji Konishi, Tatsuo Inoue, Akira Yokoyama
    Abstract:

    To achieve high and selective target radioactivity localization by monoclonal antibodies (Mabs) labeled with metallic radionuclides, the discriminated release of a hippurate-like radiometal chelate in nontarget tissues was performed using chemically modified Mabs. Methods: The disulfide Bonds of a Mab against osteogenic sarcoma (OST7, IgG 1 ) were reduced and 67 Ga chelate of succinyldeferoxamine (SDF) was conjugated proximal to the Mab molecule via an Ester Bond with exposed thiol groups ( 67 Ga-DFO-MESS-redOST7), which would impair Esterase access to the Ester Bond of 67 Ga-DFO-MESS-redOST7 due to the steric interference induced by bulky antibody molecule, stabilizing the Ester Bond in plasma and on the target cell's surface

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  • Solid-Phase Synthesis of Cyclic Depsipeptides Containing a Tyrosine Phenyl Ester Bond
    Organic Letters, 2016
    Co-Authors: Cristina Rosés, Cristina Camó, Kristy Vogels, Marta Planas, Lidia Feliu
    Abstract:

    The first solid-phase strategy for the synthesis of cyclic depsipeptides containing a phenyl Ester linkage in their structure is described. The key steps of the synthesis were the formation of the phenyl Ester Bond and the on-resin head-to-side-chain cyclization. The amino acid configuration significantly influenced the formation and the stability of the cyclic depsipeptides. The presence of a l-Tyr1 and a d-Tyr7 led to the most stable sequences.