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Enhancement of 67 Cu‐2IT‐BAT‐LYM‐1 therapy in mice with human burkitt's lymphoma (Raji) using interleukin‐2
Author(s) -
DeNardo Gerald L.,
Kukis David L.,
DeNardo Sally J.,
Shen Sui,
Mausner Leonard F.,
O'Donnell Robert T.,
Lamborn Kathleen R.,
Meyers Frederick J.,
Srivastava Suresh C.,
Miers Laird A.
Publication year - 1997
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/(sici)1097-0142(19971215)80:12+<2576::aid-cncr33>3.0.co;2-7
Subject(s) - raji cell , radioimmunotherapy , medicine , lymphoma , biodistribution , gastroenterology , pharmacology , in vivo , monoclonal antibody , immunology , antibody , biology , microbiology and biotechnology
Abstract BACKGROUND Lymphomas have been shown to be responsive to 131 I immunoconjugates in studies conducted in mice and patients. We have observed that copper 67 ( 67 Cu)‐labeled Lym‐1 remains in lymphomatous tissue longer than 131 I‐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 67 Cu‐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 67 Cu. Mice with Raji xenografts were treated with 335‐500 μCi (12.4‐18.0 MBq) of 67 Cu‐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 67 Cu‐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 67 Cu‐2IT‐BAT‐Lym‐1 with and without rIL‐2. RESULTS In mice treated with 335 μCi of 67 Cu‐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 μCi of 67 Cu‐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 67 Cu‐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 μCi or 400 μCi doses of 67 Cu‐2IT‐BAT‐Lym‐1 by rIL‐2 nor were other toxicity parameters. Mortality was increased at 500 μCi by the addition of rIL‐2. CONCLUSIONS 67 Cu‐2IT‐BAT‐Lym‐1 provided a therapeutic and frequently curative dose of radiation to tumored mice at tolerated doses. The therapeutic effectiveness of 67 Cu‐2IT‐BAT‐Lym‐1 may have been enhanced by rIL‐2. Cancer 1997; 80:2576‐82. © 1997 American Cancer Society.