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M9490102.TXT
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1994-09-03
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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).