Pharmacokinetics of chimeric L6 conjugated to indium-111- and yttrium-90-DOTA-peptide in tumor-bearing mice.
A bifunctional chelating agent, DOTA-Gly3-L-(p-isothiocyanato)-phenylalanine amide (DOTA-peptide-NCS), was studied in nude mice 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 immunoconjugates had greater tumor uptake and slower clearances.


CONCLUSIONS
Indium-111- and 90Y-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 is enhanced and a favorable therapeutic index is achieved using these agents.
DeNardo
S J
SJ
Department of Internal Medicine, University of California, Davis, USA.
Zhong
G R
GR
Salako
Q
Q
Li
M
M
DeNardo
G L
GL
Meares
C F
CF
D000818:Animals; D001345:Autoradiography; D005260:Female; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use
D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid