Targeting Chemokine Receptor CCR4 in Adult T-Cell Leukemia-Lymphoma and Other T-Cell Lymphomas

Department of Hematology, and Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.
Current Hematologic Malignancy Reports (Impact Factor: 2.29). 04/2012; 7(3):235-40. DOI: 10.1007/s11899-012-0124-3
Source: PubMed

ABSTRACT Peripheral T-cell lymphoma (PTCL) is a group of lymphoid malignancy that remains difficult to treat, as most PTCL becomes refractory or relapses, and thus there is an unmet medical need for novel treatment modalities. CC chemokine receptor 4 (CCR4) is expressed in various types of PTCL including adult T-cell leukemia-lymphoma (ATL), which has the worst prognosis among them. A phase II study of a defucosylated, humanized anti-CCR4 monoclonal antibody, mogamulizumab (KW-0761), yielded an overall response rate of 50 % (13/26) and a median progression-free survival of 5.2 months in relapsed patients with CCR4-positive ATL who had been previously treated with chemotherapy. Mogamulizumab also showed potential efficacy for cutaneous T-cell lymphoma in a US phase I/II study. Further preclinical and clinical investigations are needed to examine whether concomitant use of this novel agent with other agents with different mechanisms of action would be more effective for ATL and other PTCLs.

Download full-text


Available from: Kensei Tobinai, Jun 21, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The chemokine superfamily consists of a large number of ligands and receptors. At first glance, this family appears redundant and their ligand-receptor relationships promiscuous, making its study challenging. However, analyzing this family from the evolutionary perspective greatly simplifies understanding both the organization and function of this apparently complex system. In particular, the functions of a subgroup of chemokines (designated homeostatic chemokines) have played pivotal roles in advancing our understanding of the organization and function of the cellular networks that shape the immune system. Here, we update the full scope of the human and mouse chemokine superfamilies and their relationships and summarize several important roles that homeostatic chemokines play in the immune system.
    Immunity 05/2012; 36(5):705-16. DOI:10.1016/j.immuni.2012.05.008 · 19.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Non‐Hodgkin lymphomas (NHLs) are malignant neoplasms of lymphoid cells, the predominant cells of the immune system. This term encompasses lymphocytes and their precursor as well as their progeny cells and natural killer cells. The defining characteristics of NHLs are their gene and microribonucleic acid (miRNA) expression patterns, which differ for each lymphoma subtype and also from those of closely related normal cell types. This is a consequence of a broad range of genetic changes – including gross changes at chromosomal level, namely translocations, whole or partial chromosome losses and other, smaller changes in individual genes ranging from point mutations to deletions that result in modifications of the molecular pathways of cells that cause corresponding modifications in cell behaviour. The genetic changes that give rise directly to NHLs are induced by physical, chemical or biological environmental agents (rarely, genetic changes that predispose to lymphomas may be inherited or present from birth) or the presence of viral sequences capable of modifying normal gene expression pattern and/or molecular pathways in the relevant cell type. At the clinical level, the behaviour of malignant lymphomas varies from indolent to aggressive. Lymphomas may be observed, treated with chemotherapy or with various combinations of chemotherapy, radiation and occasionally surgery (e.g. splenectomy).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We previously produced a recombinant version of the human anti-RhD antibody Fog-1 in the rat myeloma cell line, YB2/0. When human, autologous RhD-positive red blood cells (RBC) were sensitised with this IgG1 antibody and re-injected, they were cleared much more rapidly from the circulation than had been seen earlier with the original human-mouse heterohybridoma-produced Fog-1. Since the IgG have the same amino acid sequence, this disparity is likely to be due to alternative glycosylation that results from the rat and mouse cell lines. By comparing the in vitro properties of YB2/0-produced Fog-1 IgG1 and the same antibody produced in the mouse myeloma cell line NS0, we now have a unique opportunity to pinpoint the cause of the difference in ability to clear RBC in vivo. Using transfected cell lines that express single human FcγR, we showed that IgG1 made in YB2/0 and NS0 cell lines bound equally well to receptors of the FcγRI and FcγRII classes but that the YB2/0 antibody was superior in FcγRIII binding. When measuring complexed IgG binding, the difference was 45-fold for FcγRIIIa 158F, 20-fold for FcγRIIIa 158V and approximately 40-fold for FcγRIIIb. The dissimilarity was greater at 100-fold in monomeric IgG binding assays with FcγRIIIa. When used to sensitise RBC, the YB2/0 IgG1 generated 100-fold greater human NK cell antibody-dependent cell-mediated cytotoxicity and had a 103-fold advantage over the NS0 antibody in activating NK cells, as detected by CD54 levels. In assays of monocyte activation and macrophage adherence/phagocytosis, where FcγRI plays major roles, RBC sensitised with the two antibodies produced much more similar results. Thus, the alternative glycosylation profiles of the Fog-1 antibodies affect only FcγRIII binding and FcγRIII-mediated functions. Relating this to the in vivo studies confirms the importance of FcγRIII in RBC clearance.
    PLoS ONE 10/2014; 9(10):e109463. DOI:10.1371/journal.pone.0109463 · 3.53 Impact Factor