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Effective Therapy for a Murine Model of Adult T-Cell Leukemia with the Humanized Anti-CD52 Monoclonal Antibody, Campath-1H

Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1374 [Z. Z., M. Z., C. K. G., T. A. W.], and Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York 10021 [J. V. R.]

	ABSTRACT

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Adult T-cell leukemia (ATL) develops in a small proportion of human T-cell leukemia virus I-infected individuals. Presently, there is no effective therapy for ATL. A murine model of ATL was produced by introducing leukemic cells (MET-1) from an ATL patient into nonobese diabetic/severe combined immunodeficient mice. The MET-1 cells are activated T cells that express CD2, CD3, CD4, CD25, CD122, and CD52. We evaluated the efficacy of Campath-1H (alemtuzumab; a humanized monoclonal antibody directed to CD52), alone and in combination with humanized anti-Tac (HAT) directed to CD25 (interleukin 2 receptor ) or with MEDI-507 directed to CD2. We observed that four weekly treatments with 4 mg/kg HAT significantly prolonged survival of MET-1-bearing mice. However, the survival of mice receiving 4 weeks of 4 mg/kg Campath-1H was significantly longer than that of the group receiving four weekly treatments with HAT (P < 0.001). Treatment with Campath-1H for 4 weeks led to a striking prolongation of the survival of MET-1 ATL-bearing mice that was comparable with that of tumor-free nontreated controls. Using Fc receptor (FcR) ^-/- mice, we found that FcRs on polymorphonuclear leukocytes and monocytes are required for Campath-1H-mediated tumor killing in vivo. These results demonstrate that Campath-1H has therapeutic efficacy on ATL in vivo in that the life span of the Campath-1H treatment group was comparable with that of mice that did not receive a tumor or therapy. The main tumor killing mechanism with Campath-1H in vivo involves FcR-containing receptors (e.g., FcRIII) on polymorphonuclear leukocytes and macrophages that mediate antibody-dependent cellular cytotoxicity and/or trigger cross-linking induced apoptosis. This study provides support for a clinical trial of Campath-1H in the treatment of patients with T-cell leukemias and lymphomas.

	INTRODUCTION

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ATL² develops in a small proportion of HTLV-I-infected individuals (1) . At present, there is no effective therapy for ATL, and patients progress to death with a median survival duration of 9 months for those with acute ATL and 24 months for those with chronic ATL (2) . The conventional therapies (i.e., multidrug chemotherapy regimens or zidovudine with IFN-) do not appear to prolong the life of patients with ATL (2 , 3) . A murine model of ATL was developed by introducing leukemic cells (MET-1) from an ATL patient into NOD/SCID mice (4) . New therapeutic agents have been tested in this model before initiating clinical trials (4, 5, 6) . The MET-1 ATL cells in this model are activated T cells that express CD2, CD3 dim, CD4, CD122, and CD25. They also highly express CD52. In earlier studies, anti-CD25 mAbs (e.g., murine and HAT) were tested in this model with promising results. Furthermore, clinical trials showed that HAT-based immunotherapies manifested efficacy in the therapy of patients with ATL. In the present study, we targeted CD52 on the human xenograft MET-1 ATL cells using a humanized mAb, Campath-1H (alemtuzumab).

CD52 is a glycosylated protein with a large complex N-oligosaccharide that is attached to the cell membrane by a glycosylphosphatidylinositol anchor (7, 8, 9) . The molecular weight of CD52 is approximately 21,000–28,000. The function of CD52 is unknown. Some data indicated that CD52 is involved in T-cell activation through the CD2 pathway or through T-cell receptor-dependent signal transduction (10 , 11) . CD52 is expressed on peripheral blood lymphocytes, monocytes, and macrophages with weak expression on neutrophils (11 , 12) . Campath-1H is a humanized antibody that is directed against CD52. It has been used for the treatment of refractory chronic lymphocytic leukemia (13) and for the prevention of graft-versus-host disease associated with bone marrow transplantation (14) . It is also active against T-cell prolymphocytic leukemia (15) . Infectious complications are the most significant side effects associated with its usage. Other side effects are fevers, chills, nausea, and vomiting.

In this study, we investigated the efficacy of Campath-1H in a xenograft ATL model when used alone and in combination with HAT (an anti-CD25 antibody) or with MEDI-507 (humanized antibody directed to CD2). The scientific basis for these combinations is that Campath-1H, MEDI-507, and HAT target distinct cell surface receptors (CD52, CD2, and CD25, respectively) that are expressed on the MET-1 ATL cells, an observation that suggested that they might manifest additive or synergistic efficacy. We were particularly interested in the mechanism underlying the tumor killing action mediated by Campath-1H on ATL in vivo. We demonstrated that the efficacy was lost in FcR^-/- mice, suggesting that the expression of the receptor FcRIII that utilizes the FcR chain is required for the effective action of this mAb in the mouse leukemia model.

	MATERIALS AND METHODS

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Mouse Model of ATL.
Female NOD/SCID mice were purchased from The Jackson Laboratory (Bar Harbor, ME). The mice were used in studies at the age of 6–12 weeks. Leukemia was established by i.p. injection of 15 x 10⁶ freshly isolated MET-1 cells. Mice were randomly assigned to each group when their sIL-2R levels reached a range of 1,000–10,000 pg/ml serum. These levels were observed at approximately 10–14 days after tumor inoculation, at which time treatments were initiated. In the second set of studies, the tumor burdens were higher and involved double the sIL-2R level when compared with the first set of studies. sIL-2R levels were from 1,000 to 25,000 pg/ml serum in the second set of studies. The FcR knockout mice were generated in the laboratory of Jeffrey Ravetch (Rockefeller University, New York, NY). In the study directed toward defining the mechanism involved in tumor killing, very large tumor burdens were used in the FcR knockout and FcR intact NOD/SCID mice. In these latter studies, mice with sIL-2R levels of 20,000–90,000 pg/ml serum (mean 80,000 pg/ml) were randomly assigned to the study groups for the experiments.

Measurement of sIL-2R and Soluble ß₂µ by ELISA.
Throughout the therapy experiments, the serum concentrations of soluble human IL-2R and human ß₂µ, which were used as surrogate tumor markers, were measured using ELISA kits purchased from R&D Systems (Minneapolis, MN). The ELISA tests were performed as suggested in the manufacturer’s kit inserts. The more sensitive and more accurate marker human sIL-2R was used as the pretherapy entry parameter, but ß₂µ was used posttherapy because HAT interacts with sIL-2R, precluding its accurate assessment.

Analysis of the Binding of Campath-1H to MET-1 ATL Cells.
The binding of Campath-1H to CD52 was analyzed by flow cytometry before the therapeutic experiments were conducted. The MET-1 leukemic cells were prepared for phenotypic analysis in the same fashion used in the phenotypic analysis performed in Ref. 4 . The cells were stained with the primary antibody, Campath-1H, or rituximab on ice for 30 min. They were washed and then stained with a FITC-labeled antibody directed against the human IgG Fc fragment. After washing, the cells were analyzed for the binding of Campath-1H directed to CD52 on the MET-1 cells using a Becton Dickinson FACSort Flow Cytometer.

mAbs.
The humanized mAb Campath-1H that recognizes CD52 was obtained from Ilex Pharmaceuticals (San Antonia, TX), whereas MEDI-507 against CD2 was a gift from BioTransplant Inc. (Charlestown, MA). HAT (daclizumab, Zenapax), a humanized mAb directed toward the IL-2R chain CD25), and HuMikß1, an antibody (anti-CD122) directed to the IL-2 and IL-15 binding sites of the IL-2/15Rß subunit, were obtained from Hoffmann-La Roche (Nutley, NJ). Rituximab was obtained from IDEC Pharmaceuticals (San Diego, CA).

Treatment with Antibodies.
For the evaluation of therapeutic efficacy, groups of 10 NOD/SCID mice each were injected with 10 million MET-1 leukemic cells i.p. and randomly assigned to groups that had comparable levels of the surrogate tumor marker, the serum sIL-2R (Tac, CD25). In the small tumor burden trial, the animals were treated when their sIL-2R levels ranged from 1–10,000 pg/ml (10–14 days after introduction of MET-1 leukemic cells into the mice). The groups of mice were given PBS, Campath-1H, HAT, or the combination of Campath-1H with HAT at a dose of 100 µg of each mAb i.v. weekly for 4 weeks.

In the large tumor burden trial, mice were treated when their sIL-2R levels ranged from 1,000 to 25,000 pg/ml. The groups of 10 mice were given PBS, Campath-1H, HAT, MEDI-507, or the combination of Campath-1H with MEDI-507 or with HAT at a dose of 4 mg/kg (100 µg/mouse) of each mAb i.v. weekly for 4 weeks. A final group of NOD/SCID mice was included that did not receive a tumor or a therapeutic agent to serve as a tumor-free and treatment-free control. In a study to define the mechanism of action of Campath-1H, the mAb was given weekly for 4 weeks by i.p. injection to FcR^-/- mice and to FcR intact mice. Throughout the studies, the leukemic progression was evaluated using an ELISA assay for human ß₂µ in the serum as well as by monitoring the survival of the mice using Kaplan-Meier analysis.

Statistics.
StatView was used to generate Kaplan-Meier cumulative survival plots. The unpaired t test was conducted in the analysis of ß₂µ levels.

	RESULTS

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Demonstration of Campath-1H Binding to CD52 Expressed on MET-1 ATL Cells
Using fluorescence-activated cell-sorting analysis, we demonstrated that Campath-1H binds to MET-1 ATL cells (Fig. 1A) , in contrast with the lack of reactivity of the B-cell-specific, anti-CD20 mAb, rituximab (Fig. 1B) . In additional studies, the levels of expression of CD2 and CD25 were comparable with those of CD52.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. The binding of Campath-1H to MET-1 ATL cells was evaluated by fluorescence-activated cell-sorting analysis. The MET-1 ATL cells were harvested as described in "Materials and Methods." The primary mAbs used were humanized anti-CD20 and Campath-1H. The secondary antibody was a rat antihuman IgG Fc fragment conjugated with FITC. In A, the primary antibody was Campath-1H directed to CD52. The isotype control is represented by the solid area, whereas the line represents the humanized anti-CD52. In B, the solid area represents the isotype control, and the line represents humanized anti-CD20.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Inhibition of the growth of MET-1 ATL cells in NOD/SCID mice with a small tumor burden by HAT and Campath-1H. MET-1 ATL cells were transferred into mice. The groups (10 mice/group) included those receiving PBS, four weekly doses of 4 mg/kg (100 µg/mouse) Campath-1H, four weekly doses of 4 mg/kg HAT, four weekly doses of 4 mg/kg HuMikß1 (anti-IL-2Rß), and a 4-week combination of 4 mg/kg each of Campath-1H and HAT. The data represent the mean concentration of human ß2µ in ng/ml. The 4-week Campath-1H-treated group, 4-week HAT-treated group, and the group treated with a 4-week combination of Campath-1H with HAT had significantly decreased values of ß2µ when compared with those of the PBS control group (P < 0.05). There was no significant difference in survival between the groups receiving four weekly dose of HuMikß1 and PBS (P = nonsignificant).

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Kaplan-Meier survival plot of MET-1-bearing NOD/SCID mice with a small tumor burden. The groups (10 mice/group) included those receiving i.v. PBS, 4 mg/kg HAT, 4 mg/kg HuMikß1, 4 mg/kg Campath-1H per week for 4 weeks and the combination of 4 mg/kg Campath-1H with 4 mg/kg HAT, respectively, for 4 weeks. Survival in the treated groups was followed out to 284 days. The 4-week HAT-treated group, the 4-week Campath-1H-treated group, and the group treated with the 4-week combination of Campath-1H with HAT had significantly prolonged survival when compared with the PBS control group (P < 0.001). The combination treatment of tumor-bearing mice with Campath-1H and HAT for 4 weeks significantly prolonged the survival of the group when compared with the 4-week HAT treatment group (P < 0.05).

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. Inhibition of the growth of MET-1 ATL cells in NOD/SCID mice with a large tumor burden by Campath-1H, MEDI-507, and HAT. MET-1 ATL cells were transferred into mice. The groups (10 mice/group) included those receiving PBS, four weekly doses of 4 mg/kg Campath-1H, four weekly doses of 4 mg/kg MEDI-507, four weekly doses of 4 mg/kg HAT, and a 4-week combination of 4 mg/kg each of Campath-1H with MEDI-507 or with HAT. The data represent the mean concentration of human ß2µ in ng/ml. The 4-week Campath-1H-treated group, the 4-week HAT-treated group, and the group treated with the 4-week combination of Campath-1H with MEDI-507 or with HAT had significantly decreased values of ß2µ when compared with those of the PBS control group (P < 0.001).

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Fig. 5. Kaplan-Meier survival plot of MET-1-bearing NOD/SCID mice with large tumor burden. The groups (10 mice/group) included those receiving i.v. PBS, 4 mg/kg HAT, 4 mg/kg MEDI-507, 4 mg/kg Campath-1H per week for 4 weeks and combination of 4 mg/kg Campath-1H and 4 mg/kg MEDI-507 or with 4 mg/kg HAT, respectively, for 4 weeks. The survival in treatment groups was followed out to 350 days. The 4-week HAT-treated group, 4-week MEDI-507-treated group, 4-week Campath-1H-treated group, and the group treated with the 4-week combination of Campath-1H with MEDI-507 or with HAT had significantly prolonged survivals when compared with that of the PBS control group (P < 0.001). Treatment with Campath-1H alone, MEDI-507 alone, and combination treatment of tumor-bearing mice with Campath-1H and MEDI or HAT for 4 weeks significantly prolonged the survival of the group when compared with the 4-week HAT treatment group (P < 0.05).

	FcR Expression Is Required for Effective Campath-1H Action

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View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 6. Kaplan-Meier survival plot of MET-1 FcR knockout and FcR intact ATL-bearing NOD/SCID mice. MET-1 ATL cells were transferred into mice. Once the mice developed sIL-2R levels of 20,000–90,000 pg/ml (reflecting a very large tumor burden), therapy with Campath-1H antibody was initiated. The groups (10 mice/group) included those receiving PBS or 4 weeks of 4 mg/kg/week Campath-1H in the FcR knockout ATL-bearing mice (B). In the parallel FcR intact ATL-bearing NOD/SCID mice, the groups (10 mice/group) included those receiving PBS or 4 weeks of i.p. (A) 4 mg/kg of weekly Campath-1H. Survival was followed out to 40 days. There was no significant statistical difference in survival between the group receiving four weekly doses of Campath-1H and that receiving PBS in the FcR knockout mice. In contrast, in FcR intact ATL-bearing NOD/SCID mice, the survival of the group receiving four weekly doses of Campath-1H was prolonged when compared with that of the control group.

	DISCUSSION

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Several mechanisms could theoretically be involved in the action of Campth-1H in the MET-1 ATL model. These include CDC and ADCC. CDC appears to be excluded in the present model because the mice lack human complement, because there is only a limited amount of murine complement expressed in the NOD/SCID mice used, and because complement manifests poor lysing action on MET-1 ATL cells (4) . Classical ADCC mediated by NK cells also does not appear to be a likely mode of action in this model because the NOD/SCID mice used as the recipients of ATL cells in our study virtually lacked functional NK cells.

The analysis of the efficacy of Campath-1H in FcR^-/- mice was very instructive. FcR is required for the expression of FcRIII, the stimulatory FcR. Efficacy of Campath-1H was observed in FcR intact MET-1 ATL-bearing mice but not in FcR knockout mice bearing MET-1 ATL. This observation supports the view that although multiple mechanisms have been suggested for the antitumor action of antibodies in vivo, in the case of Campath-1H, there is a dominant and necessary role played by a FcR-dependent mechanism. This FcR-dependent mechanism could theoretically involve ADCC mediated by FcRIII-expressing macrophages or granulocytes. Alternatively, it could reflect FcR-bound antibody-mediated cross-linking of the target receptors leading to apoptosis. The efficacy of Campath-1H in the MET-1 ATL model parallels the previously reported requirement for FcR expression for an effective therapeutic response to trastuzumab and rituximab as well as to a mAb directed to a melanoma antigen in murine models of breast, B-cell, and melanoma malignancies, respectively (17 , 18) . In the present study comparing mAb efficacy in FcR knockout with FcR intact animal groups, the tumor burden at the onset of therapy was more than 10 times greater than that of mice in the initial trials of this study. Thus Campath-1H can significantly delay the progression of human leukemic xenografts in mice with very large ATL burdens, supporting the view that the application of Campath-1H to the therapy of ATL may be of value in the clinic. In summary, the humanized mAb Campath-1H effectively controlled leukemia in a human leukemia xenograft model through a FcR-requiring process presumably mediated by effector cells including monocytes and granulocytes that express FcRIII. These studies provide support for a clinical trial of Campath-1H in patients with ATL and potentially in patients with other malignances that express CD52.

	ACKNOWLEDGMENTS

 
We gratefully acknowledge Ilex Pharmaceuticals for providing the Campath-1H for the studies.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at Metabolism Branch, National Cancer Institute, NIH, Building 10, Room 4N115, 10 Center Drive, Bethesda, MD 20892-1374. Phone: (301) 496-6656; Fax: (301) 496-9956; E-mail: tawald{at}helix.nih.gov

² The abbreviations used are: ATL, adult T-cell leukemia; HAT, humanized anti-Tac; HTLV, human T-cell leukemia virus; SCID, severe combined immunodeficient; NOD, nonobese diabetic; mAb, monoclonal antibody; IL, interleukin; sIL-2R, soluble IL-2 receptor ; IL-2R, IL-2 receptor ; FcR, Fc receptor; CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cellular cytotoxicity; ß₂µ, ß₂-microglobulin; HuMikß1, humanized Mikß1; NK, natural killer.

Received 4/10/03. Revised 7/ 7/03. Accepted 7/11/03.

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				M. Zhang, Z. Zhang, K. Garmestani, C. K. Goldman, J. V. Ravetch, M. W. Brechbiel, J. A. Carrasquillo, and T. A. Waldmann Activating Fc Receptors Are Required for Antitumor Efficacy of the Antibodies Directed toward CD25 in a Murine Model of Adult T-Cell Leukemia Cancer Res., August 15, 2004; 64(16): 5825 - 5829. [Abstract] [Full Text] [PDF]

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