title: Pretargeting radioimmunotherapy of a murine model of adult T-cell leukemia with the alpha-emitting radionuclide, bismuth 213.
abstract: We used a pretargeting technique to treat a nonobese diabetic/severe combined immunodeficient murine model of human adult T-cell leukemia with an anti-Tac antibody-streptavidin (HAT-SA) conjugate, which recognizes CD25, followed by bismuth 213 ((213)Bi)-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)- biotin. In the 3-step pretargeting radioimmunotherapy protocol, HAT-SA (140 or 400 microg) was administered intravenously (i.v.) to bind to the interleukin 2 receptor alpha (IL-2R alpha; CD25)-expressing tumor cells. After 24 hours, 100 microg of a synthetic clearing agent was administered i.v. to remove unbound circulating HAT-SA conjugate from the circulation. Four hours later, (213)Bi-DOTA-biotin was administered i.v. for therapy. Tumor growth was significantly inhibited in 3 trials by using 250 microCi (9.25 MBq) of (213)Bi-DOTA-biotin with a pretargeting technique as monitored by serum levels of soluble IL-2R alpha and/or human beta-2-microglobulin (P <.05, t test) and by survival of tumor-bearing mice in the treatment groups (P <.02, log rank test) as compared with the control groups. No prolongation of survival was observed with a nonspecific antibody-SA conjugate or in the absence of the radionuclide. Additionally, no prolongation of survival resulted from administration of (213)Bi directly linked to intact HAT. Furthermore, there was no prolongation of survival when the beta-emitting radionuclide yttrium 90 instead of the alpha-emitting radionuclide (213)Bi was used. The pretargeting approach with (213)Bi inhibited tumor growth more effectively than did immunotherapy with unmodified HAT. The best results were obtained with combination therapy that involved (213)Bi-DOTA-biotin with a pretargeting technique supplemented by 4 weekly doses of HAT. The findings of this study support the use of this combination approach in a clinical trial in patients with IL-2R alpha-expressing leukemias.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Meili
authors.initials: M
authors.lastname: Zhang
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Yao
authors.forename: Kayhan
authors.initials: K
authors.lastname: Garmestani
authors.forename: Donald B
authors.initials: DB
authors.lastname: Axworthy
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mallett
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Theodore
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Goldman
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Carrasquillo
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D000512:Alpha Particles; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D001710:Biotin; D001729:Bismuth / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D006573:Heterocyclic Compounds, 1-Ring; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000532:radiotherapy*; D051379:Mice; D016688:Mice, Inbred NOD; D009374:Neoplasms, Experimental / Q000628:therapy; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D015375:Receptors, Interleukin-2 / Q000276:immunology; D019809:Streptavidin; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D006573:Heterocyclic Compounds, 1-Ring; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D015375:Receptors, Interleukin-2; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D001710:Biotin; D019809:Streptavidin; D001729:Bismuth