Pharmacokinetics of chimeric L6 conjugated to indium-111- and yttrium-90- DOTA-peptide in tumor-bearing mice

S. J. DeNardo, G. R. Zhong, Q. Salako, M. Li, Gerald L Denardo, C. F. Meares

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

A bifunctional chelating agent, DOTA-Gly3-L-(p- isothiocyanato)phenylalanine amide (DOTA-peptide-NCS), was studied in nude mica bearing human breast cancer xenographs (HBT 3477) to determine its potential for radioimmunoconjugate therapy. Methods: Indium-111 and yttrium- 90 were attached to an anti-adenocarcinoma chimeric L6 (ChL6) monoclonal antibody (MAb) after pre-chelation to the DOTA-peptide-NCS and the desired neutral radiochelates were obtained by purification. The unique characteristic of the DOTA-peptide-NCS to form neutral complexes with trivalent metals was utilized to separate the resulting 111In and 90Y radiochelates from excess chelating agent and other anionic by-products resulting from metal impurities. The purified radiochelates were then conjugated to ChL6. The pharmacokinetics of 111In- and 90Y-DOTA-peptide- ChL6 were obtained for 5 days after injection in nude mice bearing HBT 3477 xenographs. The results were compared with the pharmacokinetics of 125I- ChL6 obtained in the same mouse model. Results: The whole-body clearance of 125I-ChL6, 90Y-and 111In-DOTA-peptide-ChL6 was monoexponential with biologic half-times of 92, 104 and 160 hr, respectively. Blood clearances of the three radiopharmaceuticals were biphasic. The radiometal immunoconjugatas had greater tumor uptake and slower clearances. Conclusion: Indium-111- and 89Y-DOTA-peptide-ChL6 can be produced at high specific activity with fewer than one chelate per MAb by using a pro-labeling method that permits radiochelate purification by charge selection. Studies in mouse xenografts indicate that tumor uptake is enhanced and a favorable therapeutic index is achieved using these agents.

Original languageEnglish (US)
Pages (from-to)829-836
Number of pages8
JournalJournal of Nuclear Medicine
Volume36
Issue number5
StatePublished - 1995

Fingerprint

Yttrium
Indium
Pharmacokinetics
Peptides
Neoplasms
Chelating Agents
Metals
Monoclonal Antibodies
Immunoconjugates
Radiopharmaceuticals
Heterografts
Nude Mice
Adenocarcinoma
Breast Neoplasms
Injections
Therapeutics

Keywords

  • bifunctional chelating agents
  • breast carcinoma
  • indium-111
  • monoclonal antibody
  • pharmacokinetics
  • radioimmunoconjugate therapy
  • yttrium- 90

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Pharmacokinetics of chimeric L6 conjugated to indium-111- and yttrium-90- DOTA-peptide in tumor-bearing mice. / DeNardo, S. J.; Zhong, G. R.; Salako, Q.; Li, M.; Denardo, Gerald L; Meares, C. F.

In: Journal of Nuclear Medicine, Vol. 36, No. 5, 1995, p. 829-836.

Research output: Contribution to journalArticle

DeNardo, S. J. ; Zhong, G. R. ; Salako, Q. ; Li, M. ; Denardo, Gerald L ; Meares, C. F. / Pharmacokinetics of chimeric L6 conjugated to indium-111- and yttrium-90- DOTA-peptide in tumor-bearing mice. In: Journal of Nuclear Medicine. 1995 ; Vol. 36, No. 5. pp. 829-836.
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abstract = "A bifunctional chelating agent, DOTA-Gly3-L-(p- isothiocyanato)phenylalanine amide (DOTA-peptide-NCS), was studied in nude mica bearing human breast cancer xenographs (HBT 3477) to determine its potential for radioimmunoconjugate therapy. Methods: Indium-111 and yttrium- 90 were attached to an anti-adenocarcinoma chimeric L6 (ChL6) monoclonal antibody (MAb) after pre-chelation to the DOTA-peptide-NCS and the desired neutral radiochelates were obtained by purification. The unique characteristic of the DOTA-peptide-NCS to form neutral complexes with trivalent metals was utilized to separate the resulting 111In and 90Y radiochelates from excess chelating agent and other anionic by-products resulting from metal impurities. The purified radiochelates were then conjugated to ChL6. The pharmacokinetics of 111In- and 90Y-DOTA-peptide- ChL6 were obtained for 5 days after injection in nude mice bearing HBT 3477 xenographs. The results were compared with the pharmacokinetics of 125I- ChL6 obtained in the same mouse model. Results: The whole-body clearance of 125I-ChL6, 90Y-and 111In-DOTA-peptide-ChL6 was monoexponential with biologic half-times of 92, 104 and 160 hr, respectively. Blood clearances of the three radiopharmaceuticals were biphasic. The radiometal immunoconjugatas had greater tumor uptake and slower clearances. Conclusion: Indium-111- and 89Y-DOTA-peptide-ChL6 can be produced at high specific activity with fewer than one chelate per MAb by using a pro-labeling method that permits radiochelate purification by charge selection. Studies in mouse xenografts indicate that tumor uptake is enhanced and a favorable therapeutic index is achieved using these agents.",
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T1 - Pharmacokinetics of chimeric L6 conjugated to indium-111- and yttrium-90- DOTA-peptide in tumor-bearing mice

AU - DeNardo, S. J.

AU - Zhong, G. R.

AU - Salako, Q.

AU - Li, M.

AU - Denardo, Gerald L

AU - Meares, C. F.

PY - 1995

Y1 - 1995

N2 - A bifunctional chelating agent, DOTA-Gly3-L-(p- isothiocyanato)phenylalanine amide (DOTA-peptide-NCS), was studied in nude mica bearing human breast cancer xenographs (HBT 3477) to determine its potential for radioimmunoconjugate therapy. Methods: Indium-111 and yttrium- 90 were attached to an anti-adenocarcinoma chimeric L6 (ChL6) monoclonal antibody (MAb) after pre-chelation to the DOTA-peptide-NCS and the desired neutral radiochelates were obtained by purification. The unique characteristic of the DOTA-peptide-NCS to form neutral complexes with trivalent metals was utilized to separate the resulting 111In and 90Y radiochelates from excess chelating agent and other anionic by-products resulting from metal impurities. The purified radiochelates were then conjugated to ChL6. The pharmacokinetics of 111In- and 90Y-DOTA-peptide- ChL6 were obtained for 5 days after injection in nude mice bearing HBT 3477 xenographs. The results were compared with the pharmacokinetics of 125I- ChL6 obtained in the same mouse model. Results: The whole-body clearance of 125I-ChL6, 90Y-and 111In-DOTA-peptide-ChL6 was monoexponential with biologic half-times of 92, 104 and 160 hr, respectively. Blood clearances of the three radiopharmaceuticals were biphasic. The radiometal immunoconjugatas had greater tumor uptake and slower clearances. Conclusion: Indium-111- and 89Y-DOTA-peptide-ChL6 can be produced at high specific activity with fewer than one chelate per MAb by using a pro-labeling method that permits radiochelate purification by charge selection. Studies in mouse xenografts indicate that tumor uptake is enhanced and a favorable therapeutic index is achieved using these agents.

AB - A bifunctional chelating agent, DOTA-Gly3-L-(p- isothiocyanato)phenylalanine amide (DOTA-peptide-NCS), was studied in nude mica bearing human breast cancer xenographs (HBT 3477) to determine its potential for radioimmunoconjugate therapy. Methods: Indium-111 and yttrium- 90 were attached to an anti-adenocarcinoma chimeric L6 (ChL6) monoclonal antibody (MAb) after pre-chelation to the DOTA-peptide-NCS and the desired neutral radiochelates were obtained by purification. The unique characteristic of the DOTA-peptide-NCS to form neutral complexes with trivalent metals was utilized to separate the resulting 111In and 90Y radiochelates from excess chelating agent and other anionic by-products resulting from metal impurities. The purified radiochelates were then conjugated to ChL6. The pharmacokinetics of 111In- and 90Y-DOTA-peptide- ChL6 were obtained for 5 days after injection in nude mice bearing HBT 3477 xenographs. The results were compared with the pharmacokinetics of 125I- ChL6 obtained in the same mouse model. Results: The whole-body clearance of 125I-ChL6, 90Y-and 111In-DOTA-peptide-ChL6 was monoexponential with biologic half-times of 92, 104 and 160 hr, respectively. Blood clearances of the three radiopharmaceuticals were biphasic. The radiometal immunoconjugatas had greater tumor uptake and slower clearances. Conclusion: Indium-111- and 89Y-DOTA-peptide-ChL6 can be produced at high specific activity with fewer than one chelate per MAb by using a pro-labeling method that permits radiochelate purification by charge selection. Studies in mouse xenografts indicate that tumor uptake is enhanced and a favorable therapeutic index is achieved using these agents.

KW - bifunctional chelating agents

KW - breast carcinoma

KW - indium-111

KW - monoclonal antibody

KW - pharmacokinetics

KW - radioimmunoconjugate therapy

KW - yttrium- 90

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