Twenty Years with Monoclonal Antibodies: State of the art-Where do we go?

Stigbrand, Torgny; Ullén, Anders; Sandström, Per; Mirzaie-Joniani, Homa; Sundström, Birgitta; Nillson, Bo; Ärlestig, Lisbeth; Norrlund, Rauni Rossi; Åhlström, Katrine Riklund; Hietala, Sven‐Ola

doi:10.3109/02841869609101639

Cited by 17 publications

(5 citation statements)

References 15 publications

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“…Monoclonal antibodies (mAbs) have been produced which bind to antigens present on a large number of tumor types. mAbs have been labeled with radiometals for diagnosis and therapy of cancer, and this has been a subject in many reviews published in the last 10 years. ,,− Intact mAbs are large proteins with a MW of 160 kDa, and because of their large size, they have very slow biological clearance and are excreted through the hepatobiliary system. To circumvent these drawbacks, mAb fragments have been produced that have molecular weights ranging from 10 to 100 kDa.…”

Section: Radiolabeled Monoclonal Antibodies For Tumor Imagingmentioning

confidence: 99%

Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging

1999

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Section: Radiolabeled Monoclonal Antibodies For Tumor Imagingmentioning

confidence: 99%

Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging

1999

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“…[1][2][3][4] For radioimaging, an ideal reagent should clear rapidly so that the background is minimal, producing a high signal-to-noise ratio. [5][6][7] In contrast, radioimmunotherapy strives to achieve optimal tumor targeting as its primary objective to obtain therapeutic levels of the radionuclide in the tumor mass.…”

Section: Introductionmentioning

confidence: 99%

Tumor Targeting Properties of Indium-111 Labeled Genetically Engineered Fab′ and F(ab′)₂ Constructs of Chimeric Tumor Necrosis Treatment (chTNT)-3 Antibody

Khawli

Alauddin²,

et al. 2003

Cancer Biotherapy and Radiopharmaceuticals

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Genetic engineering techniques have allowed the construction of Fab' and F(ab')2 constructs of chimeric tumor necrosis treatment antibody (chTNT-3), a chimeric monoclonal antibody (MAb) that targets necrotic regions of solid tumors. The purpose of this study is to evaluate the in vitro and in vivo properties of Fab' and F(ab')2 constructs radiolabeled with indium-111 (111In) using diethylentriamine pentaacetic acid (DTPA) conjugation to develop a clinically useful imaging agent for the detection of necrosis in solid tumors. Optimization of the MAb-to-DTPA ratio showed that a 1:2 ratio gave the best immunoreactivity while providing good radiolabeling efficiency and high specific activity for all three DPTA conjugates. In addition, 111In-labeled Fab' and F(ab')2 conjugates were found to have faster whole body clearance times and better biodistribution profiles compared to parental 111In-labeled chTNT-3 in tumor-bearing mice. Although radiolabeled Fab' and F(ab')2 constructs showed lower tumor uptake than radiolabeled chTNT-3, biodistribution results showed that these constructs had significantly lower uptake in liver, spleen, and other normal organs (except the kidney), and therefore had higher tumor-to-organ ratios. In addition, a comparison of all derivatives showed that the F(ab')2 reagent gave the best results in tumor imaging studies. These results demonstrate that stable, a genetically engineered F(ab')2 construct can be successfully radiolabeled with 111In to produce potential imaging reagents for the imaging and monitoring of tumor necrosis.

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“…Radiolabeled mAbs have not proven to be the “magic bullets” that they were once hoped to be. Although many clinical studies have been conducted with radiolabeled mAbs, problems associated with low tumor concentrations, heterogeneous deposition in tumors, and unacceptably high bone marrow and normal organ toxicity, have kept radiolabeled mAbs from being an effective treatment for cancer ( − ). A significant contributor to these problems is the long residence time of the radiolabeled antibody in blood.…”

Section: Discussionmentioning

confidence: 99%

Trifunctional Conjugation Reagents. Reagents That Contain a Biotin and a Radiometal Chelation Moiety for Application to Extracorporeal Affinity Adsorption of Radiolabeled Antibodies

et al. 2002

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A method of removing radiolabeled monoclonal antibodies (mAbs) from blood using a device external to the body, termed extracorporeal affinity-adsorption (EAA), is being evaluated as a means of decreasing irradiation of noncancerous tissues in therapy protocols. The EAA device uses an avidin column to capture biotinylated-radiolabeled mAbs from circulated blood. In this investigation, three trifunctional reagents have been developed to minimize the potential deleterious effect on antigen binding brought about by the combination of radiolabeling and biotinylation of mAbs required in the EAA approach. The studies focused on radiolabeling with 111In and 90Y, so the chelates CHX-A‘ ‘-DTPA and DOTA, which form stable attachments to these radionuclides, were incorporated in the trifunctional reagents. The first trifunctional reagent prepared did not incorporate a group to block the biotin cleaving enzyme biotinidase, but the two subsequent reagents coupled aspartic acid to the biotin carboxylate for that purpose. All three reagents used 4,7,10-trioxa-1,13-tridecanediamine as water-soluble spacers between an aminoisophthalate core and the biotin or chelation group. The mAb conjugates were radioiodinated to evaluate cell binding as a function of substitution. Radioiodination was used so that a direct comparison with unmodified mAb could be made. Evaluation of the number of conjugates per antibody versus cell binding immunoreactivities indicated that minimizing the number of conjugates was best. Interestingly, a decrease of radioiodination yield as a function of the number of isothiocyanate containing conjugates per mAb was noted. The decreased yields were presumably due to the presence of thiourea functionality formed in the conjugation reaction. Radiolabeling with 111In and 90Y was facile at room temperature for conjugates containing the CHX-A‘ ‘, but elevated temperature (e.g., 45 °C) was required to obtain good yields with the DOTA chelate. Stability of 90Y labeled mAb in serum, and when challenged with 10 mM EDTA, was high. However, challenging the 90Y labeled mAb with 10 mM DTPA demonstrated high stability for the DOTA containing conjugate, but low stability for the CHX-A‘ ‘ containing conjugate. Thus, the choice between these two chelating moieties might be made on requirements for facile and gentle labeling versus very high in vivo stability. Application of the trifunctional biotinylation reagents to the blood clearance of labeled antibodies in EAA is under investigation. The new reagents may also be useful for other applications.

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Twenty Years with Monoclonal Antibodies: State of the art-Where do we go?

Cited by 17 publications

References 15 publications

Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging

Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging

Tumor Targeting Properties of Indium-111 Labeled Genetically Engineered Fab′ and F(ab′)₂ Constructs of Chimeric Tumor Necrosis Treatment (chTNT)-3 Antibody

Trifunctional Conjugation Reagents. Reagents That Contain a Biotin and a Radiometal Chelation Moiety for Application to Extracorporeal Affinity Adsorption of Radiolabeled Antibodies

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Twenty Years with Monoclonal Antibodies: State of the art-Where do we go?

Cited by 17 publications

References 15 publications

Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging

Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging

Tumor Targeting Properties of Indium-111 Labeled Genetically Engineered Fab′ and F(ab′)2 Constructs of Chimeric Tumor Necrosis Treatment (chTNT)-3 Antibody

Trifunctional Conjugation Reagents. Reagents That Contain a Biotin and a Radiometal Chelation Moiety for Application to Extracorporeal Affinity Adsorption of Radiolabeled Antibodies

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Tumor Targeting Properties of Indium-111 Labeled Genetically Engineered Fab′ and F(ab′)₂ Constructs of Chimeric Tumor Necrosis Treatment (chTNT)-3 Antibody