Cure of human carcinoma xenografts by a single dose of pretargeted yttrium-90 with negligible toxicity

Cure of human carcinoma xenografts by a single dose of pretargeted yttrium-90 with negligible toxicity

NeoRx Corporation, Seattle, WA 98119

Communicated by M. Frederick Hawthorne, University of California, Los Angeles, CA (received for review June 21, 1999)

Abstract

A covalent conjugate (NR-LU-10/SA) was prepared between streptavidin (SA) and NR-LU-10, a mAb that binds an antigen expressed on the surface of most human carcinomas. NR-LU-10/SA was injected into nude mice bearing human tumor xenografts. Injection of biotinylated galactosyl-human serum albumin reduced the circulating levels of conjugate by 95%. Subsequent administration of ⁹⁰Y-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-biotin achieved peak uptake at the tumor within 2 hr while >80% of the radioactivity was eliminated in the urine. A single dose of 600–800 μCi of ⁹⁰Y-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-biotin produced cures in 10/10 mice with established (>200 mm³) s.c. human small cell lung or colon cancer xenografts and 8/10 cures in mice with human breast cancer xenografts without significant toxicity.

Footnotes

↵ * To whom reprint requests should be addressed at: 410 West Harrison Street, Seattle, WA 98119. E-mail: daxworthy{at}neorx.com.
Abbreviations:

SA,

streptavidin;

RIT,

radioimmunotherapy;

DOTA,

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid;

HSA,

human serum albumin;

i.d.,

injected dose;

CA,

clearing agent;

MTD,

maximum tolerable dose;

AUC,

area under curve