title: Human anti-CCR4 minibody gene transfer for the treatment of cutaneous T-cell lymphoma.
abstract: BACKGROUND
  Although several therapeutic options have become available for patients with Cutaneous T-cell Lymphoma (CTCL), no therapy has been curative. Recent studies have demonstrated that CTCL cells overexpress the CC chemokine receptor 4 (CCR4).
  
  
  RESULTS
  In this study, a xenograft model of CTCL was established and a recombinant adeno-associated viral serotype 8 (AAV8) vector expressing a humanized single-chain variable fragment (scFv)-Fc fusion (scFvFc or "minibody") of anti-CCR4 monoclonal antibody (mAb) h1567 was evaluated for curative treatment. Human CCR4+ tumor-bearing mice treated once with intravenous infusion of AAV8 virions encoding the h1567 (AAV8-h1567) minibody showed anti-tumor activity in vivo and increased survival. The AAV8-h1567 minibody notably increased the number of tumor-infiltrating Ly-6G+ FcγRIIIa(CD16A)+ murine neutrophils in the tumor xenografts over that of AAV8-control minibody treated mice. Furthermore, in CCR4+ tumor-bearing mice co-treated with AAV8-h1567 minibody and infused with human peripheral blood mononuclear cells (PBMCs), marked tumor infiltration of human CD16A+ CD56+ NK cells was observed. The h1567 minibody also induced in vitro ADCC activity through both mouse neutrophils and human NK cells.
  
  
  CONCLUSIONS
  Overall, our data demonstrate that the in vivo anti-tumor activity of h1567 minibody is mediated, at least in part, through CD16A+ immune effector cell ADCC mechanisms. These data further demonstrate the utility of the AAV-minibody gene transfer system in the rapid evaluation of candidate anti-tumor mAbs and the potency of h1567 as a potential novel therapy for CTCL.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Han
authors.forename: Ussama M
authors.initials: UM
authors.lastname: Abdel-Motal
authors.forename: De-Kuan
authors.initials: DK
authors.lastname: Chang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Sui
authors.forename: Asli
authors.initials: A
authors.lastname: Muvaffak
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhu
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Marasco
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000627:therapeutic use*; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D060888:Real-Time Polymerase Chain Reaction; D054398:Receptors, CCR4 / Q000378:metabolism*; D057127:Single-Chain Antibodies / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D000911:Antibodies, Monoclonal; C515354:CCR4 protein, human; D017931:DNA Primers; D007141:Immunoglobulin Fc Fragments; D054398:Receptors, CCR4; D057127:Single-Chain Antibodies