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 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

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