title: IL-2Ralpha-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-2Ralpha interaction.
abstract: 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-2Ralpha, 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-2Ralpha) and soluble human beta2-microglobulin (beta2mu) by ELISA. The disease progressed to death in the mice after approximately 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-2Ralpha, 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-2Ralpha 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-2Ralpha of the high affinity receptor, the 7G7/B6 monoclonal antibody binds to a different epitope on the IL-2Ralpha 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.
authors.affiliation: Metabolism Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892-1374, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Phillips
authors.forename: B
authors.initials: B
authors.lastname: Herring
authors.forename: L A
authors.initials: LA
authors.lastname: Wilson
authors.forename: M S
authors.initials: MS
authors.lastname: Rickford
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: C K
authors.initials: CK
authors.lastname: Goldman
authors.forename: J Y
authors.initials: JY
authors.lastname: Tso
authors.forename: T A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D015458:Leukemia, T-Cell / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D001613:beta 2-Microglobulin / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D015375:Receptors, Interleukin-2; D001613:beta 2-Microglobulin; D003165:Complement System Proteins