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Title: Human Anti-CCR4 Minibody Gene Transfer for the Treatment of Cutaneous T-Cell Lymphoma
Authors: Han, Thomas K;Abdel-Motal, Ussama M.;Chang, De-Kuan;Sui, Jianhua;Muvaffak, Asli;Campbell, James J.;Zhu, Quan Karen;Kupper, Thomas Seth;Marasco, Wayne A.
subject: Biology;Biotechnology;Drug Discovery;Immunology;Immunomodulation;Model Organisms;Animal Models;Mouse;Medicine;Clinical Immunology;Immunity;Immunotherapy;Immunoglobulins;Dermatology;Skin Neoplasms;Hematology;Hematologic Cancers and Related Disorders;Lymphomas
Year: 2012
Publisher: Public Library of Science
Description: 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). Methodology/Principal Findings 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/Significance: 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.
Standard no: Han, Thomas, Ussama M. Abdel-Motal, De-Kuan Chang, Jianhua Sui, Asli Muvaffak, James Campbell, Quan Zhu, Thomas S. Kupper, and Wayne A. Marasco. 2012. Human anti-CCR4 minibody gene transfer for the treatment of cutaneous T-cell lymphoma. PLoS ONE 7(9): e44455.
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