title: Radioimmunotherapy of nude mice bearing a human interleukin 2 receptor alpha-expressing lymphoma utilizing the alpha-emitting radionuclide-conjugated monoclonal antibody 212Bi-anti-Tac.
abstract: The efficacy, specificity, and toxicity of bismuth (212Bi) alpha particle-mediated radioimmunotherapy was evaluated in nude mice bearing a murine lymphoma transfected with the human CD25 [human Tac; interleukin 2 receptor alpha (IL-2R alpha)] gene. The therapeutic agent used was the tumor-specific humanized monoclonal antibody anti-Tac conjugated to 212Bi. The human IL-2R alpha-expressing cell line was produced by transfecting the gene encoding human Tac into the murine plasmacytoma cell line SP2/0. The resulting cell line, SP2/Tac, expressed approximately 18,000 human IL-2R alpha molecules/cell. Following s.c. or i.p. injection of 2 x 10(6) SP2/Tac cells into nude mice, rapidly growing tumors developed in all animals after a mean of 10 and 13 days, respectively. The bifunctional chelate cyclohexyldiethylenetriaminepentaacetic acid was used to couple 212Bi to the humanized anti-Tac monoclonal antibody. This immunoconjugate was shown to be stable in vivo. Specifically, in pharmacokinetic studies in nude mice, the blood clearance patterns of i.v. administered 205/206Bi-anti-Tac and coinjected 125I-anti-Tac were comparable. The toxicity and therapeutic efficacy of 212Bi-anti-Tac were evaluated in nude mouse ascites or solid tumor models wherein SP2/Tac cells were administered either i.p. or s.c., respectively. The i.p. administration of 212Bi-anti-Tac, 3 days following i.p. tumor inoculation, led to a dose-dependent, significant prolongation of tumor-free survival. Doses of 150 or 200 microCi prevented tumor occurrence in 75% (95% confidence interval, 41-93%) of the animals. In the second model, i.v. treatment with 212Bi-anti-Tac 3 days following s.c. tumor inoculation also resulted in a prolongation of the period before tumor development. However, prevention of tumor occurrence decreased to 30% (95% confidence interval, 11-60%). In both the i.p. and s.c. tumor trials, 212Bi-anti-Tac was significantly more effective for i.p. (P2 = 0.0128 50/100 microCi 212Bi-anti-Tac versus 50/100 microCi Mik beta; P2 = 0.0142 150/200 microCi anti-Tac versus 150/200 microCi Mik beta) and for s.c. tumors (P2 = 0.0018 100 microCi anti-Tac versus 100 microCi Mik beta; P2 = 0.0042 200 microCi anti-Tac versus 200 microCi Mik beta 1) than the control antibody Mik beta 1 coupled to 212Bi at comparable dose levels. In contrast to the efficacy observed in the adjuvant setting, therapy of large, established s.c. SP-2/Tac-expressing tumors with i.v. administered 212Bi-anti-Tac (at doses up to 200 microCi/animal) failed to induce tumor regression.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Metabolism Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.
authors.forename: F
authors.initials: F
authors.lastname: Hartmann
authors.forename: E M
authors.initials: EM
authors.lastname: Horak
authors.forename: K
authors.initials: K
authors.lastname: Garmestani
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: M W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: R W
authors.initials: RW
authors.lastname: Kozak
authors.forename: J
authors.initials: J
authors.lastname: Tso
authors.forename: S A
authors.initials: SA
authors.lastname: Kosteiny
authors.forename: O A
authors.initials: OA
authors.lastname: Gansow
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001729:Bismuth / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D004306:Dose-Response Relationship, Immunologic; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011868:Radioisotopes / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D011868:Radioisotopes; D015375:Receptors, Interleukin-2; D001729:Bismuth