An Improved Generator for the Production of <sup>213</sup>Bi from <sup>225</sup>Ac

Wu, Chao‐Liang; Brechbiel, Martin W.; Gansow, Otto A.

doi:10.1524/ract.1997.79.2.141

Cited by 57 publications

(46 citation statements)

References 10 publications

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“…The 213 Bi was eluted from a 225 Ac generator (38). The 225 Ac (Oak Ridge National Laboratories, Oak Ridge, TN) was dissolved in 0.1 M HNO 3 and loaded onto an MP-50 cation exchange resin preequilibrated with 0.1 M HNO 3 .…”

Section: Methodsmentioning

confidence: 99%

Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin

Yao¹,

Zhang²,

Garmestani³

et al. 2004

Clinical Cancer Research

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Purpose: The use of an ␣ emitter for radioimmunotherapy has potential advantages compared with ␤ emitters. When administered systemically optimal targeting of intact antibodies requires >24 h, therefore limiting the use of shortlived ␣ emitters. This study investigated the biodistribution of bismuth-labeled biotin in A431 tumor-bearing mice pretargeted with antibody B3-streptavidin (B3-SA) and examined the therapeutic efficacy of the ␣ emitter, 213Bi-labeled biotin. Experimental Design: Biotinidase-resistant 7,10-tetraazacyclododecane-N,N,N؆,Nٟ-tetraacetic acid (DOTA)-biotin was radiolabeled with 205,206 Bi or 213 Bi. Treatment of tumor-bearing mice began by administration of B3-SA (400 g) to target the tumor sites for 24 h. Then, an agent containing biotin and galactose groups was used to clear the conjugate from the circulation. Four h later, bismuth-radiolabeled DOTA-biotin was given, and biodistribution or therapy was evaluated. Dose escalation treatment from 3.7-74 MBq was performed, and the effects on tumors of different sizes were investigated. Tumor growth, complete blood cell counts, toxicity, and survival were monitored.Results: Radiolabeled biotin cleared rapidly. Rapid tumor uptake resulted in much higher tumor:nontumor targeting ratios than achieved with the directly labeled monoclonal antibody. Dose escalation revealed that 74 MBq caused acute death of mice, whereas 0.37-37 MBq doses inhibited tumor growth and prolonged survival significantly. Evidence of mild hematological toxicity was noted.At therapeutically effective doses renal toxicity was observed. Conclusions:213 Bi-DOTA-biotin, directed by the Pretarget method to tumor-targeted B3-SA, showed a therapeutic effect, although the therapeutic index was low. The source of the toxicity was most likely related to the renal toxicity.

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Section: Methodsmentioning

confidence: 99%

Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin

Yao¹,

Zhang²,

Garmestani³

et al. 2004

Clinical Cancer Research

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“…29 The MAb HuCC49DCH2 was conjugated with the CHX-A0-DTPA by established methods. 15 The conjugation reaction was performed using a tenfold molar excess of ligand to MAb to insure that a final chelate-to-protein molar ratio of ,1 was obtained. In a previous study, the conjugation of HuCC49DCH2 with a BCA had been found to severely affect the immunoreactivity of the MAb.…”

Section: Chelate Synthesis and Mab Conjugationmentioning

confidence: 99%

“…15 To the eluted 213 Bi (,1 mL), 100 mL (220 mg/mL) of ascorbic acid solution was added, and the pH of the mixture was adjusted to 4.5-5 with 5 M NH 4 OAc. HuCC49DCH2-CHX-A0 (300 mg) was then added to the 213 Bi solution.…”

Section: Radiolabeling Of Hucc49dch2mentioning

confidence: 99%

“…213 Bi is a decay product of 225 Ac and is readily obtainable from a 213 Bi/ 225 Ac generator. 15 Use of an RIC labeled with 213 Bi has already been demonstrated in clinical trials. 16,17 An added attraction to the use of 213 Bi is its 440-key a-emissions that are sufficient to perform real-time external imaging, which can be used in dosimetric calculations.…”

Section: Introductionmentioning

confidence: 99%

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Radioimmunotherapy of Human Colon Carcinoma Xenografts Using a²¹³Bi-Labeled Domain-Deleted Humanized Monoclonal Antibody

Milenic

Garmestani

Dadachova³

et al. 2004

Cancer Biotherapy and Radiopharmaceuticals

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The data presented within this paper is the first report of a humanized domain-deleted monoclonal antibody (HuCC49DeltaCH2) to be utilized in a radioimmunotherapeutic (RIT) application with 213Bi. An initial study indicated that 111In-HuCC49DeltaCH2 targets the subcutaneously implanted human colon carcinoma xenograft, LS-174T, when injected via a peritoneal route. The HuCC49DeltaCH2 was then radiolabeled with 213Bi, an alpha-emitting radionuclide with a half-life of 45.6 minutes, and evaluated for therapeutic efficacy. Dose titration studies indicated that a single dose of 500-1000 microCi, when injected by an intraperitoneal route, resulted in the growth inhibition or regression of the tumor xenograft. The radioimmunotherapeutic effect was found to be dose-dependent. Specificity of the therapeutic efficacy was confirmed in a subsequent experiment with athymic mice bearing TAG-72 negative MIP (human colorectal) xenografts. A preliminary study was also performed to assess a multiple-dose administration of 213Bi-HuCC49DeltaCH2. Doses (500 microCi) were administered at 14-day intervals after tumor implantation. A reduction in volume and/or delay in tumor growth was evident following the second and third injections of 213Bi-HuCC49DeltaCH2. As further validation of the use of 213Bi-HuCC49DeltaCH2 for RIT, a study using 131I was conducted. The overall survival of mice receiving 213Bi-HuCC49DeltaCH2 was greater than those that received 131I-HuCC49DeltaCH2.

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“…213 Bi is available through an 225 Ac/ 213 Bi generator. 33,34 An improved design of the generator has recently been reported, 35 that will permit the production of therapeutic doses for the treatment of patients. An alternate strategy is the labeling of the MAb with 225 Ac that would serve as an in vivo generator for 213 Bi.…”

Section: Discussionmentioning

confidence: 99%

In VivoEvaluation of Bismuth-Labeled Monoclonal Antibody Comparing DTPA-Derived Bifunctional Chelates

Milenic¹,

Roselli²,

Mirzadeh³

et al. 2001

Cancer Biotherapy and Radiopharmaceuticals

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Among the radionuclides considered for radioimmunotherapy, alpha-emitters such as the bismuth isotopes, 212Bi and 213Bi, are of particular interest. The macrocyclic ligand, DOTA, has been shown to form stable complexes with bismuth isotopes. The kinetics of the complexation of bismuth with the DOTA chelate, however, are slow and impractical for use with 212Bi and 213Bi that have half-lives of 60.6 and 45.6 min. The study described herein compares six DTPA derived bifunctional chelates with the goal of identifying an alternative to the DOTA ligand for radiolabeling with bismuth. Radioimmunoconjugates comprised of MAb B72.3, each of the six DTPA chelates, and radiolabeled with 206Bi, which facilitated the evaluation due to its readily detectable gamma-emission. In vitro studies showed that each of the radioimmunoconjugates retained immunoreactivity that was comparable to its 125I-labeled counterpart. The 206Bi- and 125I-labeled immunoconjugates were then co-injected i.p. into normal athymic mice. Injection of Afree@ 206Bi demonstrated that the kidneys were the critical organ to evaluate for retention of bismuth in the chelate complex. Major differences were identified among the six preparations. The CHX-A and -B immunoconjugates were found to have 1) the lowest %ID/gm in the kidney; 2) a level of 206Bi in the kidney that was comparable to that of 125I-B72.3; and 3) no significant uptake of 206Bi evident in other organs such as bone, lung and spleen. The results described herein suggest that either of the cyclohexyl derivatives of DTPA may be suitable candidates for the labeling of immunoconjugates with alpha-emitting bismuth isotopes for radioimmunotherapeutic applications.

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An Improved Generator for the Production of ²¹³Bi from ²²⁵Ac

Cited by 57 publications

References 10 publications

Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin

Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin

Radioimmunotherapy of Human Colon Carcinoma Xenografts Using a²¹³Bi-Labeled Domain-Deleted Humanized Monoclonal Antibody

In VivoEvaluation of Bismuth-Labeled Monoclonal Antibody Comparing DTPA-Derived Bifunctional Chelates

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An Improved Generator for the Production of 213Bi from 225Ac

Cited by 57 publications

References 10 publications

Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin

Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin

Radioimmunotherapy of Human Colon Carcinoma Xenografts Using a213Bi-Labeled Domain-Deleted Humanized Monoclonal Antibody

In VivoEvaluation of Bismuth-Labeled Monoclonal Antibody Comparing DTPA-Derived Bifunctional Chelates

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An Improved Generator for the Production of ²¹³Bi from ²²⁵Ac

Radioimmunotherapy of Human Colon Carcinoma Xenografts Using a²¹³Bi-Labeled Domain-Deleted Humanized Monoclonal Antibody