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

Abstract

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.

Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease

“…Other investigators have reported tumor growth inhibition and prolongation of survival in mice bearing A431 epidermoid carcinomas that were treated with anti-Ley B3 Ab-SA conjugates followed by 213 Bi-labeled DOTA-biotin. 53 Our study demonstrates that systemic therapy with 213 Bi using the PRIT approach can lead to prolonged complete remissions of lymphoma xenografts with minimal toxicities in a preclinical model.Toxicity and pharmacokinetic studies with 225 Ac-Hu195 in mice and cynomologous monkeys and with pretargeted ␣-emitters including 213 Bi and 212 Pb 53,54 suggest that renal tubular damage may be the principal toxicity of this approach. 29,55 Therefore, we evaluated the efficacy of DMPS to reduce nonspecific uptake of 213 Bi in the kidney by providing it in the drinking water.…”

Therapeutic Advantage of Pretargeted Radioimmunotherapy Using a Recombinant Bispecific Antibody in a Human Colon Cancer Xenograft

“…Renal toxicity was observed in 2 of 10 assessable animals given 900 ACi of the pretargeted 90 Y-peptide whereas other animals given this dose only had mild to moderate histologic changes, indicating that lower doses should be used. Although evidence for some degree of renal toxicity has previously been observed (26,29), other studies have not reported renal damage with doses as high as 1.0 mCi of pretargeted 90 Y-biotin, but these investigations may have been terminated prematurely or evaluated in only a small number of animals. Because the distribution of radionuclides can be monitored easily in patients by external scintigraphy, the risk for renal toxicity can be reduced by the use of dosimetry and with an understanding of radiation dose-response relationships.…”

Pharmacokinetics and toxicity of 213Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer

“…In addition to that, free bismuth-213 leached from unstable ACs is also incorporated to some extent into kidney cells. 12 Radiation nephropathy in mice was observed for 9.25 MBq of 213 Bi-DOTA-biotin 13 and for 10 MBq of 213 Bi-Fab' 14 at six months. Some mild chronic nephropathy was observed for 11.4 MBq of 213 Bi-DOTATOC.…”