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H(4)octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy.

A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCN-Bn-H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes (111)In a... Full description

Journal Title: Journal of the American Chemical Society August 28, 2013, Vol.135(34), pp.12707-12721
Main Author: Price, Eric W
Other Authors: Zeglis, Brian M , Cawthray, Jacqueline F , Ramogida, Caterina F , Ramos, Nicholas , Lewis, Jason S , Adam, Michael J , Orvig, Chris
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1520-5126 ; DOI: 10.1021/ja4049493
Link: http://search.proquest.com/docview/1428773944/?pq-origsite=primo
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title: H(4)octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy.
format: Article
creator:
  • Price, Eric W
  • Zeglis, Brian M
  • Cawthray, Jacqueline F
  • Ramogida, Caterina F
  • Ramos, Nicholas
  • Lewis, Jason S
  • Adam, Michael J
  • Orvig, Chris
subjects:
  • Animals–Chemistry
  • Antibodies, Monoclonal, Humanized–Therapeutic Use
  • Antineoplastic Agents–Chemistry
  • Chelating Agents–Therapeutic Use
  • Ethylamines–Chemistry
  • Female–Therapeutic Use
  • Heterocyclic Compounds, 1-Ring–Chemistry
  • Humans–Pharmacology
  • Indium Radioisotopes–Chemistry
  • Lutetium–Therapeutic Use
  • Mice–Chemistry
  • Mice, Nude–Therapeutic Use
  • Models, Molecular–Chemistry
  • Molecular Structure–Therapeutic Use
  • Neoplasm Transplantation–Diagnosis
  • Neoplasms, Experimental–Drug Therapy
  • Pyridines–Chemistry
  • Radiopharmaceuticals–Pharmacology
  • Tissue Distribution–Chemistry
  • Trastuzumab–Therapeutic Use
  • Tumor Cells, Cultured–Therapeutic Use
  • Xenograft Model Antitumor Assays–Therapeutic Use
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Chelating Agents
  • Ethylamines
  • Heterocyclic Compounds, 1-Ring
  • Indium Radioisotopes
  • N,N'-((6-Carboxylato)Pyridin-2-Yl)Methyl)-N,N'-Diacetic Acid-1,2-Diaminoethane
  • Pyridines
  • Radiopharmaceuticals
  • 1,4,7,10-Tetraazacyclododecane- 1,4,7,10-Tetraacetic Acid
  • Lutetium
  • Trastuzumab
ispartof: Journal of the American Chemical Society, August 28, 2013, Vol.135(34), pp.12707-12721
description: A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCN-Bn-H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes (111)In and (177)Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94-95%) than those based on DOTA-trastuzumab (60 min, 37 °C, ~50-88%). Further, antibody integrity was better preserved in the (111)In- and (177)Lu-octapa-trastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93-0.95 for (111)In- and (177)Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for (111)In- and (177)Lu-octapa-trastuzumab compared to (111)In- and (177)Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios.
language: eng
source:
identifier: E-ISSN: 1520-5126 ; DOI: 10.1021/ja4049493
fulltext: fulltext
issn:
  • 15205126
  • 1520-5126
url: Link


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titleH(4)octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy.
creatorPrice, Eric W ; Zeglis, Brian M ; Cawthray, Jacqueline F ; Ramogida, Caterina F ; Ramos, Nicholas ; Lewis, Jason S ; Adam, Michael J ; Orvig, Chris
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ispartofJournal of the American Chemical Society, August 28, 2013, Vol.135(34), pp.12707-12721
identifierE-ISSN: 1520-5126 ; DOI: 10.1021/ja4049493
subjectAnimals–Chemistry ; Antibodies, Monoclonal, Humanized–Therapeutic Use ; Antineoplastic Agents–Chemistry ; Chelating Agents–Therapeutic Use ; Ethylamines–Chemistry ; Female–Therapeutic Use ; Heterocyclic Compounds, 1-Ring–Chemistry ; Humans–Pharmacology ; Indium Radioisotopes–Chemistry ; Lutetium–Therapeutic Use ; Mice–Chemistry ; Mice, Nude–Therapeutic Use ; Models, Molecular–Chemistry ; Molecular Structure–Therapeutic Use ; Neoplasm Transplantation–Diagnosis ; Neoplasms, Experimental–Drug Therapy ; Pyridines–Chemistry ; Radiopharmaceuticals–Pharmacology ; Tissue Distribution–Chemistry ; Trastuzumab–Therapeutic Use ; Tumor Cells, Cultured–Therapeutic Use ; Xenograft Model Antitumor Assays–Therapeutic Use ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Chelating Agents ; Ethylamines ; Heterocyclic Compounds, 1-Ring ; Indium Radioisotopes ; N,N'-((6-Carboxylato)Pyridin-2-Yl)Methyl)-N,N'-Diacetic Acid-1,2-Diaminoethane ; Pyridines ; Radiopharmaceuticals ; 1,4,7,10-Tetraazacyclododecane- 1,4,7,10-Tetraacetic Acid ; Lutetium ; Trastuzumab
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descriptionA bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCN-Bn-H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes (111)In and (177)Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94-95%) than those based on DOTA-trastuzumab (60 min, 37 °C, ~50-88%). Further, antibody integrity was better preserved in the (111)In- and (177)Lu-octapa-trastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93-0.95 for (111)In- and (177)Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for (111)In- and (177)Lu-octapa-trastuzumab compared to (111)In- and (177)Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios.
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6Adam, Michael J
7Orvig, Chris
titleH(4)octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy.
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1Antibodies, Monoclonal, Humanized–Therapeutic Use
2Antineoplastic Agents–Chemistry
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5Female–Therapeutic Use
6Heterocyclic Compounds, 1-Ring–Chemistry
7Humans–Pharmacology
8Indium Radioisotopes–Chemistry
9Lutetium–Therapeutic Use
10Mice–Chemistry
11Mice, Nude–Therapeutic Use
12Models, Molecular–Chemistry
13Molecular Structure–Therapeutic Use
14Neoplasm Transplantation–Diagnosis
15Neoplasms, Experimental–Drug Therapy
16Pyridines–Chemistry
17Radiopharmaceuticals–Pharmacology
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20Tumor Cells, Cultured–Therapeutic Use
21Xenograft Model Antitumor Assays–Therapeutic Use
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23Antineoplastic Agents
24Chelating Agents
25Ethylamines
26Heterocyclic Compounds, 1-Ring
27Indium Radioisotopes
28N,N'-((6-Carboxylato)Pyridin-2-Yl)Methyl)-N,N'-Diacetic Acid-1,2-Diaminoethane
29Pyridines
30Radiopharmaceuticals
311,4,7,10-Tetraazacyclododecane- 1,4,7,10-Tetraacetic Acid
32Lutetium
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titleH(4)octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy.
authorPrice, Eric W ; Zeglis, Brian M ; Cawthray, Jacqueline F ; Ramogida, Caterina F ; Ramos, Nicholas ; Lewis, Jason S ; Adam, Michael J ; Orvig, Chris
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3Chelating Agents–Therapeutic Use
4Ethylamines–Chemistry
5Female–Therapeutic Use
6Heterocyclic Compounds, 1-Ring–Chemistry
7Humans–Pharmacology
8Indium Radioisotopes–Chemistry
9Lutetium–Therapeutic Use
10Mice–Chemistry
11Mice, Nude–Therapeutic Use
12Models, Molecular–Chemistry
13Molecular Structure–Therapeutic Use
14Neoplasm Transplantation–Diagnosis
15Neoplasms, Experimental–Drug Therapy
16Pyridines–Chemistry
17Radiopharmaceuticals–Pharmacology
18Tissue Distribution–Chemistry
19Trastuzumab–Therapeutic Use
20Tumor Cells, Cultured–Therapeutic Use
21Xenograft Model Antitumor Assays–Therapeutic Use
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