Radioimmunotherapy of cancer with radiolabeled antibodies has shown promise. A-Particles are very attractive for cancer therapy, especially for isolated malignant cells, as is observed in leukemia, because of their high linear energy transfer and short effective path length. We evaluated an anti-CD25
The PET radionuclide Cu-64 (t 1/2 = 12.7 h) can be easily produced utilizing the nuclear reaction 64 Ni( p, n) 64 Cu. A high Cu-64 production rate was obtained using high-purity enriched nickel metal on the internal tangential target of the CS-30 cyclotron. Radio-copper was isolated after column chromatography using a semi-remote apparatus. Use of reagents with little or no carrier copper yields high specific activity Cu-64 pharmaceuticals prepared from the isolated [ 64 Cu]CuCl 2 . [ 64 Cu]Cu-ATSM was prepared in greater than 1.21 ± 0.40 Ci/mmol (45 ± 15 GBq/mmol) at EOB.
IntroductionAdult T-cell leukemia (ATL) develops in a small portion of individuals infected with human T-cell lymphotrophic virus-1 (HTLV-I) and consists of an overabundance of malignant activated T cells, which are characterized by expression of the ␣ subunit of the interleukin-2 receptor (IL-2R␣; CD25) on their cell surfaces. [1][2][3][4] Presently, there is no accepted curative therapy for ATL and patients progress to death with a median survival duration of 9 months for those with acute ATL and 24 months for those with chronic ATL. 1 The observation that IL-2R␣ is not expressed by normal resting cells but is expressed by ATL cells provided the rationale for the use of monoclonal antibodies (mAbs) directed toward IL-2R␣ to deliver therapeutic agents. 5 Some partial and rare complete remissions were obtained in patients with ATL treated in clinical trials with the intact murine anti-Tac, humanized anti-Tac (daclizumab), as well as these intact antibodies armed with yttrium-90 ( 90 Y) used in an effort to develop yet more effective IL-2R␣-directed agents. 6,7 A preclinical in vivo murine model of ATL was developed by introducing leukemic cells (MET-1) from a patient with ATL into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, and new therapeutic approaches have been tested in this model before initiating human clinical trials. [8][9][10][11][12][13][14] In initial studies, antibodies to IL-2R␣ including daclizumab, murine anti-Tac, and 7G7/B6 inhibited the progression of the leukemia and prolonged survival of the leukemia-bearing mice. However, in general, cures were not achieved. 8 Therefore, more effective therapeutic approaches were required. In previous therapeutic trials, daclizumab was combined with pretargeted radioimmunotherapy in the ATL model and achieved the complementary actions of receptor-saturating doses of daclizumab to yield antibodydependent cellular cytotoxicity (ADCC) and cytokine deprivationmediated leukemic cell death along with the tumor cytoreduction provided by the radiation delivered to leukemic cell surfaces. 9,10 We also demonstrated that combining daclizumab with flavopiridol or with PS341 significantly improved therapeutic efficacy in the ATL model. 13,14 These observations suggest that for cancer therapy, the addition of 2 therapeutic agents that function via different mechanisms of action may be greater than additive in their cytotoxic action, leading to malignant cell death.In the clinical and preclinical trials, remissions have been observed using either the unmodified daclizumab monoclonal antibody at receptor-saturating doses or this antibody labeled at high specific activity with 90 Y. However, the complementary From the Metabolism Branch and the Radiation
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