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

Journal Article · Mon May 01 04:00:00 EDT 1995 · Journal of Nuclear Medicine

OSTI ID:250041

DeNardo, S J; Zhong, G R; Salako, Q ^[1]

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1. Univ. of California, Davis, CA (United States); and others

A bifunctional chelating agent, DOTA-Gly{sub 3}-L-(p-isothiocyanato)-phenylalanine amide (DOTA-peptide-NCS), was studied in nude mice bearing human breast cancer xenografts (HBT 3477) to determine its potential for radioimmunoconjugate therapy. 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 {sup 111}In and {sup 90}Y radiochelates from excess chelating agent and other anionic by-products resulting from metal impurities. The purified radiochelates were then conjugated to ChL6. The paramacokinetics of {sup 111}In- and {sup 90}Y-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 {sup 125}I-ChL6 obtained in the same mouse model. The whole-body clearance of {sup 125}I-ChL6, {sup 90}Y-and {sup 111}In-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 immunoconjugates had greater tumor uptake and slower clearances. Indium-111- and {sup 90}Y-DOTA-peptide-ChL6 can be produced at high specific activity with fewer than one chelate per MAb by using a pre-labeling method that permits radiochelate purification by charge selection. Studies in mouse xenografts indicate that tumor uptake in enhanced and a favorable therapeutic index is achieved using these agents. 29 refs., 7 figs., 2 tabs.

• DOE Contract Number: FG03-84ER60233
• OSTI ID: 250041
• Journal Information: Journal of Nuclear Medicine, Journal Name: Journal of Nuclear Medicine Journal Issue: 5 Vol. 36; ISSN 0161-5505; ISSN JNMEAQ
• Country of Publication: United States
• Language: English

Related Subjects

40 CHEMISTRY
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
BLOOD-PLASMA CLEARANCE
CHELATING AGENTS
CHEMICAL PREPARATION
CLEARANCE
INDIUM COMPLEXES
ION EXCHANGE CHROMATOGRAPHY
RADIOPHARMACEUTICALS
SPECIFICITY
TISSUE DISTRIBUTION
YTTRIUM COMPLEXES