title: Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD52 monoclonal antibody, Campath-1H.
abstract: 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 alpha) 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) gamma(-/-) mice, we found that FcRgammas 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 FcRgamma-containing receptors (e.g., FcRgammaIII) 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.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute/NIH, Building 10, Room 4N115, 10 Center Drive, Bethesda, MD 20892-1374, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Meili
authors.initials: M
authors.lastname: Zhang
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Goldman
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D000074323:Alemtuzumab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000074301:CD52 Antigen; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011897:Random Allocation; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; D017452:Receptors, IgG; D000074323:Alemtuzumab