Enhancement of 67Cu-2IT-BAT-LYM-1 therapy in mice with human Burkitt's lymphoma (Raji) using interleukin-2.
BACKGROUND
Lymphomas have been shown to be responsive to 131I immunoconjugates in studies conducted in mice and patients. We have observed that copper 67 (67Cu)-labeled Lym-1 remains in lymphomatous tissue longer than 131I-Lym-1 and, consequently, results in higher absorbed radiation doses to tumors. In addition, recombinant interleukin-2 (rIL-2) has been reported to increase tumor uptake of radiolabeled antibody. Therefore, we examined the efficacy of 67Cu-labeled Lym-1 and the ability of rIL-2 to enhance this efficacy in athymic mice implanted with Raji xenografts.


METHODS
6[p-(bromoacetamido) benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N', N'',N'''-tetraacetic acid (BAT) was conjugated to Lym-1 via 2-iminothiolane (2IT) to prepare 2IT-BAT-Lym-1, which was labeled with 67Cu. Mice with Raji xenografts were treated with 335-500 microCi (12.4-18.0 MBq) of 67Cu-2IT-BAT-Lym-1 with or without 48,000-144,000 IU of rIL-2 once or were treated b.i.d. for 5 days beginning simultaneously with 67Cu-2IT-BAT-Lym-1. Mouse weight, blood counts, and mortality were monitored to assess toxicity, and tumor size was measured to assess efficacy. In addition, groups of mice were sacrificed to assess the biodistribution of 67Cu-2IT-BAT-Lym-1 with and without rIL-2.


RESULTS
In mice treated with 335 microCi of 67Cu-2IT-BAT-Lym-1 alone, 28% of tumors were cured. When 48,000 IU of rIL-2 were added, 50% were cured. The overall response-rate was 50% for both regimens. In mice treated with 400 microCi of 67Cu-2IT-BAT-Lym-1 alone, 42% responded, all of which were cured. When 48,000 IU of rIL-2 were added, 77% of tumors responded, and 38% were cured. Larger or multiple doses of rIL-2 did not result in additional therapeutic enhancement. The tumor uptake and radiation dose after 67Cu-2IT-BAT-Lym-1 were about two times greater when a single dose of rIL-2 was added: This may be the basis for enhanced therapeutic efficacy. Mortality was not altered for 335 microCi or 400 microCi doses of 67Cu-2IT-BAT-Lym-1 by rIL-2 nor were other toxicity parameters. Mortality was increased at 500 microCi by the addition of rIL-2.


CONCLUSIONS
67Cu-2IT-BAT-Lym-1 provided a therapeutic and frequently curative dose of radiation to tumored mice at tolerated doses. The therapeutic effectiveness of 67Cu-2IT-BAT-Lym-1 may have been enhanced by rIL-2.
DeNardo
G L
GL
Division of Hematology/Oncology, University of California Davis Medical Center, Sacramento, USA.
Kukis
D L
DL
DeNardo
S J
SJ
Shen
S
S
Mausner
L F
LF
O'Donnell
R T
RT
Lamborn
K R
KR
Meyers
F J
FJ
Srivastava
S C
SC
Miers
L A
LA
D000818:Animals; D002051:Burkitt Lymphoma / Q000401:mortality / Q000532:radiotherapy*; D003301:Copper Radioisotopes / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy / Q000009:adverse effects; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D003301:Copper Radioisotopes; D007376:Interleukin-2