Document 0102
 DOCN  M9490102
 TI    Radioimmunotherapy of nude mice bearing a human interleukin 2 receptor
       alpha-expressing lymphoma utilizing the alpha-emitting
       radionuclide-conjugated monoclonal antibody 212Bi-anti-Tac.
 DT    9411
 AU    Hartmann F; Horak EM; Garmestani K; Wu C; Brechbiel MW; Kozak RW; Tso J;
       Kosteiny SA; Gansow OA; Nelson DL; et al; Metabolism Branch, National
       Cancer Institute, NIH, Bethesda,; Maryland 20892.
 SO    Cancer Res. 1994 Aug 15;54(16):4362-70. Unique Identifier : AIDSLINE
       MED/94320068
 AB    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)
 DE    Animal  Antibodies, Monoclonal/ADVERSE EFFECTS/METABOLISM/*THERAPEUTIC
       USE  Bismuth/ADVERSE EFFECTS/METABOLISM/*THERAPEUTIC USE  Dose-Response
       Relationship, Immunologic  Drug Screening Assays, Antitumor  Human
       Leukemia-Lymphoma, T-Cell, Acute, HTLV-I-Associated/IMMUNOLOGY/
       METABOLISM/*RADIOTHERAPY  Mice  Mice, Nude  Radioimmunotherapy/ADVERSE
       EFFECTS/*METHODS  Radioisotopes/ADVERSE EFFECTS/METABOLISM/*THERAPEUTIC
       USE  Radiotherapy Dosage  Receptors,
       Interleukin-2/*IMMUNOLOGY/METABOLISM  Tissue Distribution  JOURNAL
       ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).