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Experimental Therapeutics |
-Directed Monoclonal Antibodies Provide Effective Therapy in a Murine Model of Adult T-Cell Leukemia by a Mechanism other than Blockade of IL-2/IL-2R Interaction
Metabolism Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892-1374 [K. E. P., B. H., L. A. W., M. S. R., M. Z., C. K. G., T. A. W.], and Protein Design Labs, Inc., Fremont, California 94555 [J. Y. T.]
Adult T-cell
leukemia (ATL) develops in a small proportion of human T-cell
lymphotrophic virus-I infected individuals. The leukemia consists of an
overabundance of activated T cells, which are characterized by the
expression of CD25, or IL-2R
, on their cell surface. Presently,
there is not an accepted curative therapy for ATL. We developed an
in vivo model of ATL in non-obese diabetic/severe
combined immunodeficient (NOD/SCID) mice by introducing cells from an
ATL patient (MET-1) into the mice. The leukemic cells proliferated in
these mice that lack functional T, B, and natural killer (NK) cells.
The MET-1 leukemic cells could be monitored by measurements of both
serum soluble Tac (IL-2R) and soluble human
ß2-microglobulin (ß2µ) by ELISA. The
disease progressed to death in the mice after 
4–6 weeks. The mice
developed grossly enlarged spleens and a leukemia involving ATL cells
that retained the phenotype and the T-cell receptor rearrangement and
human T-cell lymphotrophic virus-I integration pattern of the
patient’s ATL leukemia cells. This model is of value for testing the
efficacy of novel therapeutic agents for ATL. The administration of
humanized anti-Tac (HAT), murine anti-Tac (MAT), and 7G7/B6, all of
which target IL-2R, significantly delayed the progression of the
leukemia and prolonged the survival of the tumor-bearing mice. In
particular, HAT induced complete remissions in 4 of 19 mice and partial
remissions in the remainder. It appears that the antibodies act by a
mechanism that had not been anticipated. The prevailing view is that
antibodies to the IL-2R receptor have their effective action by
blocking the interaction of IL-2 with its growth factor receptor,
thereby inducing cytokine deprivation apoptosis. However, although both
HAT and MAT block the binding of IL-2 to IL-2R of the high
affinity receptor, the 7G7/B6 monoclonal antibody binds to a different
epitope on the IL-2R receptor, one that is not involved in IL-2
binding. This suggested that the antibodies provide an effective
therapy by a mechanism other than induction of cytokine deprivation. In
accord with this view, the MET-1 cells obtained from the spleens of
leukemic mice did not produce IL-2, nor did they express IL-2 mRNA as
assessed by reverse transcription-PCR. Another possible conventional
mechanism of action involves complement-mediated killing. However,
although MAT and 7G7/B6 fix rabbit complement, HAT does not do so.
Furthermore, in the presence of NOD/SCID mouse serum, there was no
complement-mediated lysis of MET-1 cells. In addition, the antibodies
did not manifest antibody-dependent cellular cytotoxicity with NOD/SCID
splenocytes that virtually lack NK cells as the effector cells as
assessed in an in vitro chromium-release assay. However,
in contrast to the efficacy of intact HAT, the F(ab')2
version of this antibody was not effective in prolonging the survival
of mice injected with MET-1 ATL cells. In conclusion, in our
murine model of ATL, monoclonal antibodies, HAT, MAT, and 7G7/B6,
appear to delay progression of the leukemia by a mechanism of action
that is different from the accepted mechanism of IL-2
deprivation leading to cell death. We consider two alternatives: the
first, antibody-dependent cellular cytotoxicity mediated by FcRI- or
FcRIII-expressing cells other than NK cells, such as monocytes or
polymorphonuclear leukocytes. The second alternative we consider
involves direct induction of apoptosis by the anti-IL-2R antibodies
in vivo. It has been shown that the IL-2R is a critical
element in the peripheral self-tolerance T-cell suicide mechanism
involved in the phenomenon of activation-induced cell death.
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