title: Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD2 monoclonal antibody, MEDI-507.
abstract: Adult T-cell leukemia (ATL) develops in a small proportion of individuals infected with the retrovirus human T-cell leukemia virus (HTLV-1). We evaluated the efficacy of MEDI-507 (a humanized monoclonal antibody directed against CD2) alone and in combination with humanized anti-Tac (HAT) directed toward CD25, the interleukin-2 receptor alpha (IL-2Ralpha) using a human adult T-cell leukemia xenograft model. Weekly treatments (4) with HAT significantly prolonged the survival of the ATL-bearing mice when compared with phosphate-buffered saline (PBS)-treated controls (P <.0001). Mice treated with MEDI-507 (100 microg/wk for 4 weeks) survived longer than those treated with HAT (P <.0025). Furthermore, prolonged treatment (6 months) of ATL with MEDI-507 significantly improved the outcome when compared with a short course (4 weeks) of therapy (P <.0036). Such treatment with weekly MEDI-507 for 6 months led to a prolonged survival of the ATL-bearing mice that was comparable with the survival observed in the control group of mice that did not receive a tumor or therapeutic agent. We also found that the expression of Fcgamma receptors (FcRgamma) on polymorphonuclear leukocytes and monocytes was required for MEDI-507-mediated tumor killing in vivo. Thus, the tumor-killing mechanism with MEDI-507 in vivo required the expression of the receptor FcRgammaIII on polymorphonuclear leukocytes and monocytes, suggesting that it is mediated by a form of antibody-dependent cellular cytotoxicity. These results demonstrate that MEDI-507 has therapeutic efficacy on ATL in vivo and provides support for a clinical trial involving this monoclonal antibody in the treatment of patients with CD2-expressing leukemias and lymphomas.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute/NIH, Bldg 10, Rm 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: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
authors.forename: Carolyn
authors.initials: C
authors.lastname: Goldman
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018801:CD2 Antigens / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000235:genetics / Q000502:physiology; D018123:Receptors, Interleukin / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018801:CD2 Antigens; C508017:IL2RA protein, human; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D017452:Receptors, IgG; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; C544394:siplizumab